relación entre el VIH y el SIDA

Introducción

La definición de SIDA

El síndrome de inmunodeficiencia adquirida (SIDA) se caracteriza por la pérdida progresiva de la CD4 + helper / inductor subconjunto de linfocitos T, lo que lleva a la inmunosupresión severa y enfermedad constitucional, complicaciones neurológicas, y las infecciones y neoplasias oportunistas que rara vez se producen en personas con función inmune intacto. Aunque los mecanismos precisos que conducen a la destrucción del sistema inmune no han sido completamente delineado, abundante epidemiológica, virológica y datos inmunológicos apoyan la conclusión de que la infección con el virus de la inmunodeficiencia humana (VIH) es la causa subyacente de SIDA.

La evidencia para el papel principal de VIH en la patogénesis del SIDA se revisa en otro lugar (Ho et al, 1987;. Fauci, 1988, 1993a; Greene, 1993; Levy, 1993; Weiss, 1993). Además, muchos científicos (Blattner et al, 1988a, b;. Ginsberg, 1988; Evans, 1989a, b, 1992; Weiss y Jaffe, 1990; Gallo, 1991; Goudsmit, 1992; Groopman, 1992; Kurth, 1990; Ascher et al., 1993a, b;. Schechter et al, 1993a, b; Lowenstein, 1994; Nicoll y Brown, 1994; Harris, 1995) han respondido a los argumentos específicos de las personas que afirman que el SIDA no es causado por el VIH. El presente análisis se examina la epidemia del SIDA y resume la evidencia que apoya el VIH como la causa del SIDA.

La Denominación SIDA es una herramienta de vigilancia

El término SIDA apareció por primera vez en el Informe Semanal de Morbilidad y Mortalidad (MMWR) de los Centros para el Control de Enfermedades () en 1982 para describir “… una enfermedad, por lo menos moderadamente predictivo de un defecto en la inmunidad mediada por células, que se producen sin causa conocida para la disminución de la resistencia a la enfermedad “(, 1982b). La lista inicial de las condiciones que definen el SIDA, lo que incluye el sarcoma de Kaposi (SK), neumonía por Pneumocystis carinii (PCP), el complejo Mycobacterium avium (MAC) y otras condiciones, se ha actualizado en varias ocasiones, con revisiones significativas (1985a, 1987a, 1992a).

La cuantificación de la epidemia

Para la vigilancia, la define actualmente el SIDA en un adulto o adolescente edad de 13 años o más a partir de la presencia de una de las 25 condiciones indicadora de SIDA, como KS, PCP o diseminada MAC. En niños menores de 13 años, la definición de SIDA es similar a la de los adolescentes y los adultos, excepto que la neumonitis intersticial linfoide y las infecciones bacterianas recurrentes están incluidos en la lista de condiciones que definen el SIDA (1987b). La definición de caso en adultos y adolescentes se amplió en 1993 para incluir la infección por VIH en un individuo con una célula T CD4 + de menos de 200 células por milímetro cúbico (mm3) de sangre (1992a). Los criterios de definición reemplazado vigilancia actual publicados en 1987 que se basaron en las condiciones clínicas y pruebas de infección por VIH, pero no en la fabricación de células T CD4 + (1987a).

En muchos países en desarrollo, donde las instalaciones de diagnóstico pueden ser mínimos, epidemiólogos emplean una definición de caso basado en la presencia de varios síntomas clínicos asociados con la deficiencia inmune y la exclusión de otras causas conocidas de la inmunosupresión, como el cáncer o desnutrición (Ryder y Mugewrwa, 1994a ; Davachi, 1994).

Una breve historia de la aparición del SIDA

definiciones de vigilancia de SIDA han demostrado epidemiológicamente útil para realizar un seguimiento y cuantificar la reciente epidemia de la inmunosupresión mediada por el VIH y sus manifestaciones. Sin embargo, el SIDA representa sólo la etapa final de un proceso patogénico continua, progresiva, a partir de la infección primaria con VIH, continuando con una fase crónica que suele ser asintomática, lo que progresivamente síntomas graves y, en última instancia, profunda inmunodeficiencia y las infecciones oportunistas y neoplasmas ( Fauci, 1993a). En la práctica clínica, sintomatología y las mediciones de la función inmune, en concreto los niveles de linfocitos T CD4 +, se utilizan para guiar el tratamiento de las personas infectadas por el VIH en lugar de un paradigma de todo o nada del SIDA / sin SIDA (1992a; Sande et al, 1993;. Volberding y Graham, 1994).

Entre junio de 1981 y el 31 de diciembre de 1994, 441,528 casos de SIDA en los Estados Unidos, incluyendo 270,870 muertes relacionadas con el SIDA, se informó a la (, 1995a). SIDA es la principal causa de muerte entre los adultos de 25 a 44 años de edad en los Estados Unidos (, 1995b) (Figura 1).

Las teorías iniciales

Higo. 1. Las tasas de mortalidad de las principales causas de muerte en personas de 25-44 años, Estados Unidos, 1982-1993; Referencia: Centros para el Control y la Prevención de Enfermedades

A nivel mundial, se reportaron 1,025,073 casos de SIDA a la Organización Mundial de la Salud (OMS) hasta diciembre de 1994, un incremento del 20 por ciento desde diciembre de 1993 (OMS, 1995a) (Figura 2). Teniendo en virtud de diagnóstico, información incompleta e informar demora, y en base a los datos disponibles sobre las infecciones de VIH en todo el mundo, la OMS estima que más de 4,5 millones de casos de SIDA acumulados se han producido en todo el mundo a finales de 1994 y que 19,5 millones de personas en todo el mundo habían sido infectados con el VIH desde el comienzo de la epidemia (OMS, 1995a). Para el año 2000, la OMS estima que 30 a 40 millones de personas han sido infectadas con el VIH y que 10 millones de personas se han desarrollado SIDA (OMS, 1994). La Coalición Global de Políticas del SIDA ha desarrollado una estimación considerablemente mayor – quizás hasta 110 millones de infecciones por el VIH y 25 millones de casos de SIDA por el cambio de siglo (Mann et al., 1992a).

En 1981, los investigadores clínicos en Nueva York y California observaron entre los jóvenes, hombres homosexuales previamente sanos, una agrupación inusual de casos de enfermedades raras, especialmente el sarcoma de Kaposi (SK) e infecciones oportunistas como la neumonía por Pneumocystis carinii (PCP), así como los casos de linfadenopatía inexplicable, persistente (, 1981a, b, 1982a;. Masur et al, 1981;. Gottlieb et al, 1981; Friedman-Kien, 1981). Pronto se hizo evidente que estos hombres tenían un déficit común inmunológica, una alteración en la inmunidad mediada por células como resultado de una pérdida significativa de células “T helper”, que llevan el marcador CD4 (Gottlieb et al, 1981;. Masur et al. , 1981; Siegal et al, 1981;.. Ammann et al, 1983a).

Los numerosos casos de sarcoma de Kaposi y el PCP en personas jóvenes sin enfermedad subyacente o la historia de la terapia inmunosupresora no tenía precedentes. Las búsquedas de la literatura médica, registros de autopsia y registros de tumores revelaron que estas enfermedades hasta ahora se habían producido en niveles muy bajos en los Estados Unidos (, 1981b;, 1982f).

KS, una neoplasia de piel muy raro, había afectado a hombres de más edad en su mayoría de origen mediterráneo o los pacientes con cáncer sometidos a trasplante o tratamiento inmunosupresor (Gange y Jones, 1978; safai y Good, 1981). Antes de la epidemia del SIDA, la incidencia anual de sarcoma de Kaposi en los Estados Unidos fue de 0,02 al 0,06 100.000 habitantes (Rothman, 1962a; Oettle, 1962). Además, una forma más agresiva del sarcoma de Kaposi que por lo general se produjo en los individuos más jóvenes se observó en ciertas partes de África (Rothman, 1962b; safai, 1984a). En 1984, se encontró que los hombres nunca casadas en San Francisco para ser 2.000 veces más probabilidades de desarrollar KS que durante los años 1973 a 1979 (Williams et al., 1994). Al 31 de diciembre de 1994, 36,693 pacientes con SIDA en los Estados Unidos con un diagnóstico definitivo de KS se había informado a la (, 1995b).

PCP, una infección pulmonar causada por un patógeno al que la mayoría de los individuos están expuestos sin consecuencias indebidas, era extremadamente rara antes de 1981 en individuos distintos de los que reciben terapia inmunosupresora o entre la malnutrición crónica, tales como ciertos niños de Europa del Este después de la Segunda Guerra Mundial (Walzer, 1990). Una encuesta de 1967, por ejemplo, encontró sólo 107 casos de Estados Unidos de PCP reportado en la literatura médica hasta ese momento, prácticamente todos los individuos con condiciones subyacentes o inmunosupresores que se sometieron a terapia inmunosupresora (Le Clair, 1969). En ese año, se convirtió en el único proveedor en los Estados Unidos de isetionato de pentamidina, a continuación, la única terapia recomendada PCP, y comenzó a recoger datos sobre cada caso PCP diagnosticada y tratada en este país. Después de revisar las solicitudes de pentamidina en el período de 1967 a 1970, los investigadores encontraron un solo caso de PCP confirmado sin una condición subyacente conocida (Walzer, et al., 1974). En el período inmediatamente anterior al reconocimiento de SIDA, enero 1976 a junio 1980, recibió una única petición de isetionato de pentamidina para el tratamiento de un adulto en los Estados Unidos que tenía PCP y sin enfermedad de base (, 1982f). Sólo en 1981, se recibieron 42 solicitudes de pentamidina para el tratamiento de pacientes con PCP y no hay trastornos subyacentes conocidos (, 1982f). El 31 de diciembre de 1994, 127,626 personas con SIDA en los Estados Unidos con diagnóstico definitivo de PCP se había informado a la (, 1995b).

Otra rara enfermedad oportunista, infección diseminada con el complejo Mycobacterium avium (MAC), también fue visto con frecuencia en los primeros pacientes de SIDA (Zakowski et al, 1982;.. Greene et al, 1982). Antes de 1981, sólo 32 individuos con enfermedad diseminada por MAC habían sido descritos en la literatura médica (Masur, 1982a). El 31 de diciembre de 1994, los informes recibidos tenido de 28,954 pacientes de SIDA con EE.UU. diagnósticos definitivos de MAC diseminada (, 1995b).

El hecho de que los hombres homosexuales constituían la población inicial en la que el SIDA se produjo en los Estados Unidos llevó a algunos a suponer que un estilo de vida homosexual se relaciona específicamente con la enfermedad (Goedert et al, 1982;. Hurtenbach y Shearer, 1982;. Sonnabend et al, 1983; Durack, 1981;. Mavligit et al, 1984). Estas primeras sugerencias de que el SIDA fue resultado de un comportamiento específico a la población homosexual fueron despedidos en gran medida cuando se observó el síndrome en distintamente diferentes grupos en los Estados Unidos: en hombres y mujeres usuarias de drogas inyectables; en hemofílicos y receptores de transfusiones sanguíneas; entre las parejas sexuales femeninas de hombres bisexuales, los receptores de sangre o productos sanguíneos, o los usuarios de drogas inyectables; y entre los bebés nacidos de madres con SIDA o con un historial de uso de drogas inyectables (, 1982b, c, d, f, 1983a; Poon et al, 1983;.. Elliot et al, 1983; Masur et al, 1982b;. Davis et al, 1983;. Harris et al, 1983;. Rubinstein et al, 1983;.. Oleske et al, 1983;. Ammann et al, 1983b). En 1983, por ejemplo, un estudio encontró que los hemofílicos sin antecedentes de alguna de las causas propuestas de SIDA en hombres homosexuales habían desarrollado el síndrome, y algunos de los hombres se habían transmitido al parecer la infección a sus esposas (DeShazo et al., 1983 ).

Muchos expertos en salud pública llegó a la conclusión de que la agrupación de casos de SIDA (Auerbach et al, 1984;.. Gazzard y otros, 1984) y la aparición de casos en diversos grupos de riesgo sólo podían explicarse si el SIDA fueron causadas por un microorganismo infeccioso transmitido en el tipo de virus de la hepatitis B (VHB):.. por contacto sexual, por inoculación con sangre o productos sanguíneos, y de la madre al recién nacido (Francis et al, 1983; Curran et al, 1984; AMA, 1984;, 1982f, 1983a ,segundo).

sospechosos iniciales para la causa del SIDA eran citomegalovirus (CMV), debido a su asociación con la inmunosupresión, y el virus de Epstein-Barr (EBV), que tiene una afinidad para los linfocitos (Gottlieb et al, 1981;.. Hymes et al, 1981; , 1982f). Sin embargo, el SIDA era un fenómeno nuevo, y estos virus ya tenía una distribución mundial. estudios de seroprevalencia comparativos mostraron ninguna evidencia convincente para asignar estos virus u otros agentes conocidos un papel primordial en el síndrome de Down (Rogers et al., 1983). También faltan pruebas de que estos virus, cuando se aíslan de pacientes con SIDA, diferían significativamente de las cepas que se encuentran en individuos sanos o de las cepas encontradas en los años anteriores a la aparición del SIDA (AMA, 1984).

En 1983, varios grupos de investigación se han centrado en los retrovirus de pistas sobre la causa del SIDA (Gallo y Montagnier, 1987). Dos retrovirus recientemente reconocidas, HTLV-I y HTLV-II, fueron los únicos virus conocidos entonces para infectar preferentemente linfocitos T colaboradores, las células agotadas en las personas con SIDA (Gallo y Reitz, 1982;. Popovic et al, 1984). El patrón de transmisión del HTLV fue similar a la observada en los pacientes con SIDA: HTLV se transmite por contacto sexual, de madre a hijo o por exposición a sangre infectada (Essex, 1982; Gallo y Reitz, 1982). Además, HTLV-I se sabe que causa inmunosupresión suave, y un retrovirus relacionado, el virus de la leucemia linfotrópico felino (FeLV), causada inmunosupresión letal en los gatos (Essex et al., 1975).

En mayo de 1983, el primer informe que proporciona evidencia experimental de una asociación entre un retrovirus y el SIDA se publicó (Barre-Sinoussi et al., 1983). Después de encontrar anticuerpos de reacción cruzada con el HTLV-I en un paciente homosexual con linfadenopatía, un grupo dirigido por el Dr. Luc Montagnier aisló un virus no identificado anteriormente que contiene la transcriptasa inversa que era citopático para linfocitos de sangre de cordón (Barre-Sinoussi et al., 1983 ). Este virus más tarde llegó a ser conocido como el virus asociado a la linfadenopatía (LAV). Posteriormente, el grupo francés informó que era LAV trópico de células T auxiliares, en los cuales creció hasta títulos importantes y causó la muerte celular (Klatzmann et al, 1984a;. Montagnier et al., 1984).

En 1984, una considerable cantidad de nuevos datos añade a la evidencia de una etiología retroviral para el SIDA. Investigadores de theernment reportaron el aislamiento de un virus T-linfotrópico citopático de 48 personas diferentes, incluyendo 18 de los 21 con pre-SIDA, tres de las cuatro madres clínicamente normales de los niños con SIDA, 26 de los 72 niños y adultos con SIDA, y uno ( que más tarde desarrollaron el SIDA) de 22 homosexuales sanos (Gallo et al., 1984). El virus, llamado HTLV-III, no se pudo encontrar en 115 sujetos sanos heterosexuales.

Se encontraron anticuerpos reactivos con antígenos de HTLV-III en muestras de suero de 88 por ciento de los 48 pacientes con SIDA, 79 por ciento de 14 homosexuales con pre-SIDA, y menos de 1 por ciento de los cientos de heterosexuales sanos (Sarngadharan et al., 1984).

Poco después, los investigadores encontraron que el 100 por ciento (34 de 34) de los pacientes con SIDA analizadas fueron positivas para anticuerpos de HTLV-III en un estudio en el que ninguno de los 14 controles tenían anticuerpos (safai et al., 1984b).

En un estudio realizado en el Reino Unido informó de ese mismo año, los investigadores encontraron que 30 de 31 pacientes con SIDA probadas fueron seropositivos para anticuerpos HTLV-III, al igual que 110 de los 124 individuos con linfadenopatía generalizada persistente (Cheingsong-Popov et al., 1984). Ninguno de más de 1.000 donantes de sangre ha seleccionado al azar tenía anticuerpos para HTLV-III en este estudio.

Durante el mismo período de tiempo, el HTLV-III se aisló del semen de pacientes con SIDA (Zagury et al., 1984, Ho et al., 1984), hallazgos consistentes con los datos epidemiológicos que demuestran la transmisión del SIDA a través del contacto sexual.

Los investigadores en San Francisco informó posteriormente el aislamiento de un retrovirus que llamaron el retrovirus asociado al SIDA (ARV) a partir de pacientes de SIDA en diferentes grupos de riesgo, así como de personas asintomáticas de grupos de riesgo de SIDA (Levy et al., 1984). Los investigadores aislaron ARV de 27 de 55 pacientes con SIDA o síndrome de linfadenopatía; detectaron anticuerpos para ARV en 90 por ciento de los 113 individuos con las mismas condiciones. Como HTLV-III y LAV, ARV creció sustancialmente en las células mononucleares de sangre periférica y mató a las células T CD4 +. El mismo grupo aislado posteriormente ARV de las secreciones genitales de las mujeres con anticuerpos contra el virus, datos consistentes con la observación de que los hombres pueden contraer el SIDA tras el contacto con una mujer infectada con el virus (Wofsy et al., 1986).

Durante el mismo período, el HTLV-III y ARV fueron aisladas de los cerebros de los niños y adultos con encefalopatía asociada con el SIDA, lo que sugiere un papel para estos virus en los trastornos del sistema nervioso central se observan en muchos pacientes con SIDA (Levy et al., 1985;. Ho et al, 1985).

Por 1985, los análisis de las secuencias de nucleótidos de HTLV-III, LAV y ARV demostraron que los tres virus pertenecen a la misma familia retroviral y eran sorprendentemente similares (Wain-Hobson et al, 1985;.. Ratner et al, 1985; Sánchez Pescador et al., 1985). En 1986, el Comité Internacional de Taxonomía Viral renombró los virus del virus de la inmunodeficiencia humana (VIH) (Coffin et al., 1986).

Las pruebas serológicas para anticuerpos contra el VIH, desarrollado en 1984 (Sarngadharan et al, 1984;.. Popovic et al, 1984; revisado en Brookmeyer y Gail, 1994), han permitido a los investigadores a realizar cientos de estudios de seroprevalencia en todo el mundo. El uso de estas pruebas, los investigadores han demostrado en varias ocasiones que la aparición de enfermedades similares al SIDA en diferentes poblaciones ha seguido de cerca la aparición de anticuerpos contra el VIH (Oficina del Censo de EE.UU. del 1994). Por ejemplo, el examen retrospectivo de los sueros recogidos a finales de 1970 en asociación con los estudios de la hepatitis B en Nueva York, San Francisco y Los Ángeles sugiere que el VIH entró en la población de EE.UU. en algún momento a finales de 1970 (Jaffe et al., 1985a). En 1978, el 4,5 por ciento de los hombres en la cohorte de San Francisco tenía anticuerpos contra el VIH (Jaffe et al., 1985a). Se informó que los primeros casos de SIDA en hombres homosexuales en San Francisco en 1981, y en 1984, más de dos tercios de la cohorte de San Francisco tenían anticuerpos contra el VIH y las condiciones relacionadas con el SIDA casi un tercio había desarrollado (Jaffe et al., 1985a). A finales de 1992, aproximadamente el 70 por ciento de los 539 hombres en la cohorte de San Francisco con una fecha bien documentada de seroconversión del VIH antes de 1983 había desarrollado una condición definitoria de SIDA o tenían un recuento de células T CD4 + de menos de 200 / mm3; otro 11 por ciento tenía recuentos de células T CD4 + entre 200 y 500 / mm3 (Buchbinder et al., 1994) (Figura 3).

pruebas retrospectiva del suministro de sangre EE.UU. han demostrado que, en 1978, al menos un lote de Factor VIII estaba contaminado con el VIH (Evatt et al, 1985;. Aronson, 1993). El factor VIII fue dado a unos 2.300 hombres en los Estados Unidos ese año. En julio de 1982, se informó de los primeros casos de SIDA en hemofílicos (, 1982c). Hasta el 31 de diciembre de 1994, 3.863 personas en los Estados Unidos con hemofilia u otros trastornos de la coagulación habían sido diagnosticados con SIDA (1995a).

En otras partes del mundo, se ha observado una asociación cronológica similar entre el VIH y el SIDA. La aparición del VIH en el suministro de sangre ha precedido o coincidido con la aparición de casos de SIDA en cada país y región en la que los casos de SIDA han sido reportados (Institute of Medicine, 1986; Chin y Mann, 1988; Curran et al., 1988; Piot et al., 1988; Mann, 1992;. Mann et al, 1992; US Bureau of the Census, 1994). Por ejemplo, una revisión de las encuestas serológicas asociadas con la fiebre del dengue en el Caribe encontró que la evidencia más temprana de la infección por VIH en Haití apareció en las muestras a partir de 1979 (Pape et al, 1983, 1993.); se reportaron los primeros casos de SIDA en Haití y los haitianos en los Estados Unidos a principios de la década de 1980 (, 1982e;. Pape et al, 1983, 1993).

En África entre 1981 y 1983, las epidemias clínicas de enfermedades crónicas y potencialmente mortales enteropathic ( “delgado enfermedad”), la meningitis criptocócica, KS progresivos y la candidiasis esofágica fueron reconocidos en Ruanda, Tanzania, Uganda, Zaire y Zambia, y en 1983 la primera se reportaron casos de SIDA entre los africanos (Quinn et al, 1986;. Essex, 1994). La muestra de sangre más antigua de África del que se ha recuperado del VIH es de un posible paciente de SIDA en Zaire, probado en relación con un brote de virus Ebola 1976 (Getchell et al, 1987;. Myers et al., 1992).

datos serológicos han sugerido la presencia de la infección por VIH ya en 1959 en el Zaire (Nahmias y col., 1986). Otros investigadores han encontrado pruebas de ADN proviral del VIH en los tejidos de un marinero que murió en Manchester, Inglaterra, en 1959 (Corbitt et al., 1990). En el último caso, este hallazgo puede haber representado una contaminación con un virus aislado en una fecha muy posterior (Zhu y Ho, 1995).

VIH no se convirtió en epidemia de hasta 20 a 30 años más tarde, tal vez debido a la migración de las personas sexualmente activas pobres y jóvenes de las zonas rurales a los centros urbanos en los países en desarrollo, con la migración de retorno subsiguiente y, a nivel internacional, debido a las guerras civiles, el turismo de negocios los viajes y el tráfico de drogas (Quinn, 1994).

Como un retrovirus, el VIH es un virus de ARN que codifica para la enzima transcriptasa inversa, que transcribe el ARN genómico viral en una copia de ADN que finalmente se integra en el genoma de la célula huésped (Fauci, 1988). Dentro de la familia de los retrovirus, el VIH se clasifica como un lentivirus, que tiene similitudes genéticas y morfológicas a lentivirus animales, tales como aquellos gatos que infectan (virus de la inmunodeficiencia felina), ovejas (virus visna), cabras (caprina virus de la artritis-encefalitis), y no humana primates (virus de inmunodeficiencia simia) (Stowring et al, 1979;.. Gonda et al, 1985; Haase, 1986; Temin, 1988, 1989). Como el VIH en seres humanos, estos virus animales infectan principalmente las células del sistema inmune, incluyendo linfocitos T y macrófagos (Haase, 1986, 1990; Levy, 1993) (Tabla 1).

Referencia: Levy, 1993.

Los lentivirus a menudo causan la inmunodeficiencia en sus huéspedes, además de reducir la velocidad, trastornos de desgaste progresivo, la neurodegeneración y la muerte (Haase, 1986, 1990). SIV, por ejemplo, infecta varias subespecies de monos macacos, causando diarrea, pérdida de masa, el agotamiento de las células T CD4 +, las infecciones oportunistas y la muerte (Desrosiers, 1990; Fultz, 1993). VIH está estrechamente relacionado con SIV, como se evidencia por viral de proteínas de reactividad cruzada y similitudes de secuencia genéticos (Franchini et al, 1987;. Hirsch et al, 1989;. Desrosiers, 1990; Myers, 1992).

Una característica que distingue a los lentivirus de otros retrovirus es la notable complejidad de sus genomas virales. La mayoría de los retrovirus que son capaces de replicación contienen sólo tres genes – env, gag y pol (Varmus, 1988). VIH no sólo contiene estos genes esenciales, sino también los genes reguladores complejos tat, rev, nef, vif y genes auxiliares, vpr y vpu (Greene, 1991). Las acciones de estos genes adicionales probablemente contribuyen a la patogenicidad profunda que diferencia VIH de muchos otros retrovirus.

Hipótesis retrovirus

células T CD4 +, las células agotadas en pacientes de SIDA, son objetivos primarios del VIH debido a la afinidad del componente de glicoproteína gp120 de la envoltura viral para la molécula de CD4 (Dalgleish et al, 1984;. Klatzmann et al, 1984b;. McDougal et al., 1985a, 1986). Estos llamados células T auxiliares de coordenadas un número de funciones inmunológicas críticos. La pérdida de estas células da como resultado la alteración progresiva del sistema inmune y está asociado con un curso clínico deterioro (Pantaleo et al., 1993a). En la enfermedad avanzada por VIH, las anormalidades de prácticamente todos los componentes del sistema inmune son evidentes (Fauci, 1993a;. Pantaleo y otros, 1993a).

La infección primaria del VIH está asociado con una explosión de viremia VIH y, a menudo una disminución brusca concomitante de las células T CD4 + en la sangre periférica (Cooper et al, 1985;. Daar et al, 1991;. Tindall y Cooper, 1991; Clark et al. , 1991;. Pantaleo et al, 1993a, 1994). La disminución en la circulación de las células T CD4 + durante la infección primaria es probablemente debido tanto a la muerte celular mediada por VIH y para volver a tráfico de células a los tejidos linfoides y otros órganos (Fauci, 1993a).

La mediana del período de tiempo entre la infección con el VIH y la aparición de la enfermedad clínica es de aproximadamente 10 años en los países occidentales, de acuerdo con estudios prospectivos de hombres homosexuales en los que las fechas de seroconversión son conocidos (Lemp y otros, 1990;. Pantaleo y col. , 1993a;. Hessol et al, 1994) (Figura 4). estimaciones similares de períodos asintomáticos se han hecho para los receptores de transfusión de sangre infectados por el VIH, usuarios de drogas inyectables y hemofílicos adultos (revisado en Alcabes et al., 1993a).

la enfermedad del VIH, sin embargo, no se expresa de manera uniforme en todos los individuos. Una pequeña proporción de las personas infectadas con el virus desarrollan el SIDA y mueren a los pocos meses después de la infección primaria, mientras que aproximadamente el 5 por ciento de las personas infectadas por el VIH no muestran signos de progresión de la enfermedad, incluso después de 12 o más años (Pantaleo y otros, 1995a;. Cao et al., 1995). Los factores del huésped, como la edad o las diferencias genéticas entre individuos, el nivel de virulencia de la cepa particular del virus, así como las influencias tales como la coinfección con otros microbios pueden determinar el tipo y la gravedad de la enfermedad de expresión del VIH en personas diferentes (Fauci, 1993a;. Pantaleo et al, 1993a). Tales variables se han denominado “factores de promoción de la enfermedad clínica” o co-factores y parecen influir en la aparición de la enfermedad clínica entre los infectados con cualquier patógeno (Evans, 1982). La mayoría de las personas infectadas con la hepatitis B, por ejemplo, no muestran síntomas o solamente ictericia y despejar su infección, mientras que otros sufren enfermedades que van desde la inflamación hepática crónica a cirrosis y carcinoma hepatocelular (Robinson, 1990). Los co-factores probablemente también determinar por qué algunos fumadores desarrollan cáncer de pulmón, mientras que otros no lo hacen.

Como la enfermedad progresa, el aumento de cantidades de virus infecciosos, antígenos virales y ácidos nucleicos específicos de VIH en el cuerpo correlaciona con un curso de empeoramiento clínico (Allain et al, 1987;. Nicholson et al, 1989;. Ho et al, 1989;. Schnittman et al, 1989, 1990a, 1991;. Mathez et al, 1990;. Genesca et al, 1990;. Hufert et al, 1991;. Saag et al, 1991;. Aoki-Sei et al, 1992;. Yerly et al ., 1992; Bagnarelli et al, 1992;.. Ferre et al, 1992;. Michael et al, 1992;. Pantaleo et al, 1993b;. Gupta et al, 1993;. Connor et al, 1993; Saksela et al. , 1994; Dickover et al, 1994;.. Daar et al, 1995;. Furtado et al, 1995).

Los estudios transversales en adultos y niños han demostrado que los niveles de VIH infeccioso o material de ADN en la sangre son sustancialmente más altos en los pacientes con SIDA que en pacientes asintomáticos (Ho et al, 1989;.. Coombs et al, 1989; Saag et al ., 1991;. Srugo et al, 1991; Michael et al, 1992;.. Aoki-Sei et al, 1992). En ambos tejidos sanguíneos y linfáticos de individuos infectados por el VIH, los investigadores encontraron theernment carga viral y la replicación a ser sustancialmente mayor en los pacientes con SIDA que en pacientes en estadio temprano (Pantaleo et al., 1993b). Este grupo también encontró deterioro de la arquitectura y el microambiente del tejido linfoide en mayor medida en los pacientes en etapa tardía que en los individuos asintomáticos. La disolución de la red de células dendríticas foliculares del centro germinal de los ganglios linfáticos y la pérdida progresiva de la capacidad presentadora de antígeno son factores críticos probables que contribuyen a la deficiencia inmune que se ve en los individuos con SIDA (Pantaleo et al., 1993b).

Más recientemente, el mismo grupo estudió a 15 pacientes no progresores a largo plazo, definidos como las personas infectadas por más de siete años (por lo general más de 10 años) que no recibieron tratamiento antirretroviral y no mostró disminución de células T CD4 +. Ellos encontraron que la carga viral y la replicación viral en la sangre periférica y en los ganglios linfáticos, medida por el ADN y el ARN PCR, respectivamente, eran al menos 10 veces menor que en 18 individuos infectados por el VIH cuya progresión de la enfermedad era más típico. Además, la arquitectura de los ganglios linfáticos en los no progresores a largo plazo se mantuvo intacta (Pantaleo et al., 1995a).

Los estudios longitudinales también han cuantificado carga viral y la replicación en la sangre y su relación con la progresión de la enfermedad (Schnittman et al, 1990a;. Connor et al, 1993;. Saksela et al, 1994;.. Daar et al, 1995; Furtado et al ., 1995). En un estudio de los individuos infectados por el VIH asintomáticos que en última instancia se desarrolló rápidamente enfermedad progresiva, el número de células T CD4 + en el que el ADN del VIH se pudo encontrar aumentado con el tiempo, mientras que esto no ocurre en los pacientes con enfermedad estable (Schnittman et al., 1990a ). A partir de muestras de sangre en serie de individuos infectados con VIH que tuvieron una caída en picado de las células T CD4 +, seguido por una rápida progresión a SIDA, otros grupos encontraron un aumento significativo en los niveles de concurrentes ADN del VIH con o antes de la disminución de células T CD4 + (Connor et al, 1993;.. Daar et al, 1995). El aumento de expresión de mRNA de VIH en células mononucleares de sangre periférica también se ha demostrado que preceden progresión clínicamente definida de la enfermedad (Saksela et al., 1994).

En la cohorte del estudio longitudinal multicéntrico SIDA (MACS), homosexuales y bisexuales para quien se había documentado el momento de la seroconversión tenían niveles crecientes de ambos plasmáticos de ARN del VIH y el ARN intracelular como enfermedad progresó y tenía el número de células T CD4 + que declinaron (Gupta et al ., 1993; Mellors et al, 1995).. Los hombres que permanecieron asintomáticos con el número de células T CD4 + estables mantienen los niveles extremadamente bajos de ARN viral. Estos hallazgos sugieren que los niveles de ARN del VIH en plasma son un predictor fuerte, CD4 independiente de rápida progresión a SIDA. Otro estudio longitudinal encontró que el aumento de los niveles de ARN en plasma fueron altamente predictivo del desarrollo de resistencia a la zidovudina y muerte (AZT) en pacientes en tratamiento a largo plazo con ese medicamento (Vahey et al., 1994).

Otra evidencia sugiere que los cambios en la carga viral debido a los cambios en la terapia pueden predecir el beneficio clínico en pacientes. Recientemente se encontró que la cantidad de ARN del VIH en la sangre periférica disminuye en pacientes que cambiaron a didanosina (ddI) después de tomar el AZT y el aumento en los pacientes que continuaron tomando AZT (NTIS, 1994; Welles et al., 1995). Las disminuciones en el ARN del VIH se asociaron con un menor número de progresiones a nuevas enfermedades definitorias de sida diagnosticados previamente o muerte. Este estudio proporcionó la primera evidencia de que una reducción inducida por el tratamiento de la carga viral del VIH se asocia con el resultado clínico. Del mismo modo, los estudios de muestras de sangre recogidas en serie de pacientes infectados por el VIH encontraron que una disminución en el ARN del VIH número de copias en los primeros meses después del tratamiento con AZT fuertemente correlacionado con un mejor resultado clínico (O’Brien et al, 1994;. Jurriaans et al. , 1995).

Las encuestas de seroprevalencia

VIH y otros lentivirus

Curso de la infección por VIH

La aparición de variantes del VIH que son más citopático y replicarse en una gama más amplia de células susceptibles in vitro también se ha demostrado que se correlaciona con la progresión de la enfermedad en los individuos infectados por el VIH (Fenyo et al, 1988;.. Tersmette et al, 1988, 1989a , b; Richman y Bozzette, 1994;. Connor et al, 1993, Connor y Ho, 1994a, b). Resultados similares se han visto in vivo con macacos infectados con SIV clonado molecularmente (Kodama et al., 1993). También se ha informado de que el VIH aislados de pacientes que progresan a SIDA tienen una mayor tasa de replicación en comparación con el VIH aislados de individuos que permanecen asintomáticos (Fenyo et al., 1988; Tersmette et al., 1989a), y que las variantes de rápida replicación del VIH surgir durante la fase asintomática de la infección antes de la progresión de la enfermedad (Tersmette et al, 1989b;. Connor y Ho, 1994b).

Está bien establecido que un número de viral, rickettsial, hongos, protozoos y las infecciones bacterianas pueden causar transitorios de células T disminuye (Chandra, 1983). deficiencias inmunes debido a tumores, enfermedades autoinmunes, trastornos congénitos raros, quimioterapia y otros factores que han demostrado para poner ciertos individuos susceptibles a infecciones oportunistas (Ammann, 1991). Como se mencionó anteriormente, la desnutrición crónica después de la Segunda Guerra Mundial dio lugar a PCP en los niños de Europa del Este (Walzer, 1990). Transplant recipients treated with immunosuppressive drugs such as cyclosporin and glucocorticoids often suffer recurrent diseases due to pathogens such as varicella zoster virus and cytomegalovirus that also cause disease in HIV-infected individuals (Chandra, 1983; Ammann, 1991).

However, the specific immunologic profile that typifies AIDS–a progressive reduction of CD4+ T cells resulting in persistent CD4+ T lymphocytopenia and profound deficits in cellular immunity–is extraordinarily rare in the absence of HIV infection or other known causes of immunosuppression. This was recently demonstrated in several surveys that sought to determine the frequency of idiopathic CD4+ T-cell lymphocytopenia (ICL), which is characterized by CD4+ T cell counts lower than 300 cells per cubic millimeter (mm3) of blood in the absence of HIV antibodies or conditions or therapies associated with depressed levels of CD4+ T cells (reviewed in Fauci, 1993b; Laurence, 1993).

In a survey, only 47 (.02 percent) of 230,179 individuals diagnosed with AIDS were both HIV-seronegative and had persistently low CD4+ T cell counts (<300/MM3) in the absence of conditions or therapies associated with immunosuppression (Smith et al., 1993). In the MACS, 22,643 CD4+ T cell determinations in 2,713 HIV-seronegative homosexual men revealed only one individual with a CD4+ T cell count persistently lower than 300 cells/mm3, and this individual was receiving immunosuppressive therapy (Vermund et al., 1993a). A similar review of another cohort of homosexual and bisexual men found no case of persistently lowered CD4+ T cell counts among 756 HIV-seronegative men who had no other cause of immunosuppression (Smith et al., 1993). Analogous results were reported from the San Francisco Men's Health Study, a population-based cohort recruited in 1984. Among 206 HIV-seronegative heterosexual and 526 HIV-seronegative homosexual or bisexual men, only one had consistently low CD4+ T cell counts (Sheppard et al., 1993). This individual also had low CD8+ T cell counts, suggesting that he had general lymphopenia rather than a selective loss of CD4+ T cells. No AIDS-defining clinical condition was observed among these HIV-seronegative men. Studies of blood donors, recipients of blood and blood products, and household and sexual contacts of transfusion recipients also suggest that persistently low CD4+ T cell counts are extremely rare in the absence of HIV infection (Aledort et al., 1993; Busch et al., 1994). Longitudinal studies of injection-drug users have demonstrated that unexplained CD4+ T lymphocytopenia is almost never seen among HIV-seronegative individuals in this population, despite a high risk of exposure to hepatitis B, cytomegalovirus and other blood-borne pathogens (Des Jarlais et al., 1993; Weiss et al., 1992). HIV infects and kills CD4+ T lymphocytes in vitro, although scientists have developed immortalized T-cell lines in order to propagate HIV in the laboratory (Popovic et al., 1984; Zagury et al., 1986; Garry, 1989; Clark et al., 1991). Several mechanisms of CD4+ T cell killing have been observed in lentivirus systems in vitro and may explain the progressive loss of these cells in HIV-infected individuals (reviewed in Garry, 1989; Fauci, 1993a; Pantaleo et al., 1993a) (Table 2). These mechanisms include disruption of the cell membrane as HIV buds from the surface (Leonard et al., 1988) or the intracellular accumulation of heterodisperse RNAs and unintegrated DNA (Pauza et al., 1990; Koga et al., 1988). Evidence also suggests that intracellular complexing of CD4 and viral envelope products can result in cell killing (Hoxie et al., 1986). Direct HIV-mediated cytopathic effects (single-cell killing) HIV-mediated formation of syncytia Virus-specific immune responses HIV-specific cytolytic T lymphocytes Antibody-dependent cellular cytotoxicity Natural killer cells Autoimmune mechanisms Anergy caused by inappropriate cell signaling through gp120-CD4 interaction Superantigen-mediated perturbation of T-cell subgroups Programmed cell death (apoptosis) Reference: Pantaleo et al., 1993a. In addition to these direct mechanisms of CD4+ T cell depletion, indirect mechanisms may result in the death of uninfected CD4+ T cells (reviewed in Fauci, 1993a; Pantaleo et al., 1993a). Uninfected cells often fuse with infected cells, resulting in giant cells called syncytia that have been associated with the cytopathic effect of HIV in vitro (Sodroski et al., 1986; Lifson et al., 1986). Uninfected cells also may be killed when free gp120, the envelope protein of HIV, binds to their surfaces, marking them for destruction by antibody-dependent cellular cytotoxicity responses (Lyerly et al., 1987). Other autoimmune phenomena may also contribute to CD4+ T cell death since HIV envelope proteins share some degree of homology with certain major histocompatibility complex type II (MHC-II) molecules (Golding et al., 1989; Koenig et al., 1988). A number of investigators have suggested that superantigens, either encoded by HIV or derived from unrelated agents, may trigger massive stimulation and expansion of CD4+ T cells, ultimately leading to depletion or anergy of these cells (Janeway, 1991; Hugin et al., 1991). The untimely induction of a form of programmed cell death called apoptosis has been proposed as an additional mechanism for CD4+ T cell loss in HIV infection (Ameisen and Capron, 1991; Terai et al., 1991; Laurent-Crawford et al., 1991). Recent reports indicate that apoptosis occurs to a greater extent in HIV-infected individuals than in non-infected persons, both in the peripheral blood and lymph nodes (Finkel et al., 1995; Pantaleo and Fauci, 1995b; Muro-Cacho et al., 1995). It has also been observed that HIV infects precursors of CD4+ T cells in the bone marrow and thymus and damages the microenvironment of these organs necessary for the optimal sustenance and maturation of progenitor cells (Schnittman et al., 1990b; Stanley et al., 1992). These findings may help explain the lack of regeneration of the CD4+ T cell pool in patients with AIDS (Fauci, 1993a). Recent studies have demonstrated a substantial viral burden and active viral replication in both the peripheral blood and lymphoid tissues even early in HIV infection (Fox et al., 1989; Coombs et al., 1989; Ho et al., 1989; Michael et al., 1992; Bagnarelli et al., 1992; Pantaleo et al., 1993b; Embretson et al., 1993; Piatak et al., 1993). One group has reported that 25 percent of CD4+ T cells in the lymph nodes of HIV-infected individuals harbor HIV DNA early in the course of disease (Embretson et al., 1993). Other data suggest that HIV infection is sustained by a dynamic process involving continuous rounds of new viral infection and the destruction and replacement of over 1 billion CD4+ T cells per day (Wei et al., 1995; Ho et al., 1995). Taken together, these studies strongly suggest that HIV has a central role in the pathogenesis of AIDS, either directly or indirectly by triggering a series of pathogenic events that contribute to progressive immunosuppression. Recent developments in HIV research provide some of the strongest evidence for the causative role of HIV in AIDS and fulfill the classical postulates for disease causation developed by Henle and Koch in the 19th century (Koch's postulates reviewed in Evans, 1976, 1989a; Harden, 1992). Koch's postulates have been variously interpreted by many scientists over the years. One scientist who asserts that HIV does not cause AIDS has set forth the following interpretation of the postulates for proving the causal relationship between a microorganism and a specific disease (Duesberg, 1987) The microorganism must be found in all cases of the disease.; It must be isolated from the host and grown in pure culture.; It must reproduce the original disease when introduced into a susceptible host.; It must be found in the experimental host so infected.; Recent developments in HIV/AIDS research have shown that HIV fulfills these criteria as the cause of AIDS. 1) The development of DNA PCR has enabled researchers to document the presence of cell-associated proviral HIV in virtually all patients with AIDS, as well as in individuals in earlier stages of HIV disease (Kwok et al., 1987; Wages et al., 1991; Bagasra et al., 1992; Bruisten et al., 1992; Petru et al., 1992; Hammer et al., 1993). RNA PCR has been used to detect cell-free and/or cell-associated viral RNA in patients at all stages of HIV disease (Ottmann et al., 1991; Schnittman et al., 1991; Aoki-Sei, 1992; Michael et al., 1992; Piatak et al., 1993) (Table 3). Modified from Hammer et al., 1993. 2) Improvements in co-culture techniques have allowed the isolation of HIV in virtually all AIDS patients, as well as in almost all seropositive individuals with both early- and late-stage disease (Coombs et al., 1989; Schnittman et al., 1989; Ho et al., 1989; Jackson et al., 1990). 1-4) All four postulates have been fulfilled in three laboratory workers with no other risk factors who have developed AIDS or severe immunosuppression after accidental exposure to concentrated HIVIIIB in the laboratory (Blattner et al., 1993; Reitz et al., 1994; Cohen, 1994c). Two patients were infected in 1985 and one in 1991. All three have shown marked CD4+ T cell depletion, and two have CD4+ T cell counts that have dropped below 200/mm3 of blood. One of these latter individuals developed PCP, an AIDS indicator disease, 68 months after showing evidence of infection and did not receive antiretroviral drugs until 83 months after the infection. In all three cases, HIVIIIB was isolated from the infected individual, sequenced, and shown to be the original infecting strain of virus. In addition, as of Dec. 31, 1994, had received reports of 42 health care workers in the United States with documented, occupationally acquired HIV infection, of whom 17 have developed AIDS in the absence of other risk factors (, 1995a). These individuals all had evidence of HIV seroconversion following a discrete percutaneous or mucocutaneous exposure to blood, body fluids or other clinical laboratory specimens containing HIV. The development of AIDS following known HIV seroconversion also has been repeatedly observed in pediatric and adult blood transfusion cases (Ward et al., 1989; Ashton et al., 1994), in mother-to-child transmission (European Collaborative Study, 1991, 1992; Turner et al., 1993; Blanche et al., 1994), and in studies of hemophilia, injection drug use, and sexual transmission in which the time of seroconversion can be documented using serial blood samples (Goedert et al., 1989; Rezza et al., 1989; Biggar, 1990; Alcabes et al., 1993a,b; Giesecke et al., 1990; Buchbinder et al., 1994; Sabin et al., 1993). In many such cases, infection is followed by an acute retroviral syndrome, which further strengthens the chronological association between HIV and AIDS (Pedersen et al., 1989, 1993; Schechter et al., 1990; Tindall and Cooper, 1991; Keet et al., 1993; Sinicco et al., 1993; Bachmeyer et al., 1993; Lindback et al., 1994). A recent study demonstrated that an HIV variant that causes AIDS in humans--HIV-2--also causes a similar syndrome when injected into baboons (Barnett et al., 1994). Over the course of two years, HIV-2-infected animals exhibited a significant decline in immune function, as well as lymphocytic interstitial pneumonia (which often afflicts children with AIDS), the development of lesions similar to those seen in Kaposi's sarcoma, and severe weight loss akin to the wasting syndrome that occurs in human AIDS patients. Other studies suggest that pigtailed macaques also develop AIDS-associated diseases subsequent to HIV-2 infection (Morton et al., 1994). Asian monkeys infected with clones of the simian immunodeficiency virus (SIV), a lentivirus closely related to HIV, also develop AIDS-like syndromes (reviewed in Desrosiers, 1990; Fultz, 1993). In macaque species, various cloned SIV isolates induce syndromes that parallel HIV infection and AIDS in humans, including early lymphadenopathy and the occurrence of opportunistic infections such as pulmonary Pneumocystis carinii infection, cytomegalovirus, cryptosporidium, candida and disseminated MAC (Letvin et al., 1985; Kestler et al., 1990; Dewhurst et al., 1990; Kodama et al., 1993). In cell culture experiments, molecular clones of HIV are tropic for the same cells as clinical HIV isolates and laboratory strains of the virus and show the same pattern of cell killing (Hays et al., 1992), providing further evidence that HIV is responsible for the immune defects of AIDS. Moreover, in severe combined immunodeficiency (SCID) mice with human thymus/liver implants, molecular clones of HIV produce the same patterns of cell killing and pathogenesis as seen with clinical isolates (Bonyhadi et al., 1993; Aldrovandi et al., 1993). Convincing evidence that HIV causes AIDS also comes from the geographic correlation between rates of HIV antibody positivity and incidence of disease. Numerous studies have shown that AIDS is common only in populations with a high seroprevalence of HIV antibodies. Conversely, in populations in which HIV antibody seroprevalence is low, AIDS is extremely rare (U.S. Bureau of the Census, 1994). Malawi, a country in southern Africa with 8.2 million inhabitants, reported 34,167 cases of AIDS to the WHO as of December 1994 (WHO, 1995a). This is the highest case rate in the region. The rate of HIV seroprevalence in Malawi is also high, as evidenced by serosurveys of pregnant women and blood donors (U.S. Bureau of the Census, 1994). In one survey, approximately 23 percent of more than 6,600 pregnant women in urban areas were HIV-positive (Dallabetta et al., 1993). Approximately 20 percent of 547 blood donors in a 1990 survey were HIV-positive (Kool et al., 1990). In contrast, Madagascar, an island country off the southeast coast of Africa with a population of 11.3 million, reported only nine cases of AIDS to the WHO through December 1994 (WHO, 1995a). HIV seroprevalence is extremely low in this country; in recent surveys of 1,629 blood donors and 1,111 pregnant women, no evidence of HIV infection was found (Rasamindrakotroka et al., 1991). Yet, other sexually transmitted diseases are common in Madagascar; a 1989 seroepidemiologic study for syphilis found that 19.5 percent of 12,457 persons tested were infected (Latif, 1994; Harms et al., 1994). It is likely that due to the relative geographic isolation of this island nation, HIV was introduced late into its population. However, the high rate of other STDs such as syphilis would predict that HIV will spread in this country in the future. Similar patterns have been noted in Asia. Thailand reported 13,246 cases of AIDS to the WHO through December 1994, up from only 14 cases through 1988 (WHO, 1995a) (Figure 5). This rise has paralleled the spread of HIV infection in Thailand. Through 1987, fewer than.05 percent of 200,000 Thais from all risk groups were HIV-seropositive (Weniger et al., 1991). By 1993, 3.7 percent of 55,000 inductees into the Royal Thai Army tested positive for HIV antibodies, up from 0.5 percent of men recruited in 1989 (U.S. Bureau of the Census Database, December 1994). Seropositivity among brothel prostitutes in Thailand rose from 3.5 percent in June 1989 to 27.1 percent in June 1993 (Hanenberg et al., 1994). By mid-1993, an estimated 740,00 people were infected with HIV in Thailand (Brown and Sittitrai, 1994). By the year 2000, researchers estimate that there may be 1.4 million cumulative HIV infections and 480,000 AIDS cases in that country (Cohen, 1994b). By comparison, South Korea reported only 25 cases of AIDS to the WHO through Dec. 1994 (WHO, 1995a). In serosurveys in that country conducted in 1993, HIV seroprevalence was.008 percent among female prostitutes and.00007 percent among blood donors (Shin et al., 1994). By the end of 1994, 7,223 cumulative cases of AIDS in the United States resulting from blood transfusions or the receipt of blood components or tissue had been reported to the (, 1995a). Virtually all of these cases can be traced to transfusions before the screening of the blood supply for HIV commenced in 1985 (Jones et al., 1992; Selik et al., 1993). Compelling evidence supporting a cause-and-effect relationship between HIV and AIDS has come from studies of transfusion recipients with AIDS who have received blood from at least one donor with HIV infection. In the earliest such study (before the discovery of HIV), seven patients with transfusion-acquired AIDS were shown to have received a total of 99 units of blood components. At least one donor to each patient was identified who had AIDS-like symptoms or immunosuppression (Curran et al., 1984). With the identification of HIV and the development of serologic assays for the virus in 1984, it became possible to trace infected donors (Sarngadharan et al., 1984). The first reports of donor-recipient pairs appeared later that year (Feorino et al., 1984; Groopman et al., 1984). In one instance, HIV was isolated from both donor and recipient, and both had developed AIDS (Feorino et al., 1984); in the other, the recipient was HIV antibody-positive and had developed AIDS, and the donor had culturable virus in his blood and was in a group considered to be at high risk for AIDS (Groopman et al., 1984). Molecular analysis of HIV isolates from these donor-recipient pairs found that the viruses were slightly different but much more similar than would be expected by chance alone (Feorino et al., 1984; Groopman et al., 1984). Immunologic Profile of People With AIDS Mechanisms of CD4+ T Cell Depletion Koch's Postulates Fulfilled Evidence From Animal and Laboratory Models In a subsequent study of patients with transfusion-acquired AIDS, 28 of 28 individuals had antibodies to HIV, and each had received blood from an HIV-infected donor (Jaffe et al., 1985b). Similar results were reported from a set of 18 patients with transfusion-acquired AIDS, each of whom had received blood from an HIV-infected donor (McDougal et al., 1985b). Fifteen of the 18 donors in this study had low CD4+/CD8+ T cell ratios, an immune defect seen in pre-AIDS and AIDS patients. Another group studied seropositive recipients of blood from 112 donors in whom AIDS later developed and from 31 donors later found to be positive for HIV antibody. Of 101 seropositive recipients followed for a median of 55 months after infection, 43 developed AIDS (Ward et al., 1989). More recently, Australian investigators identified 25 individuals with transfusion-acquired HIV whose infection could be traced to eight individuals who donated blood between 1980 and 1985, and subsequently developed AIDS. By 1992, nine of the 25 HIV-infected blood recipients had developed AIDS, with progression to AIDS and death more rapid among the recipients who received blood from the faster-progressing donors (Ashton et al., 1994). As noted above, HIV has been detected in stored blood samples taken from hemophiliac patients in the United States as early as 1978 (Aronson, 1993). By 1984, 55 to 78 percent of U.S. hemophilic patients were HIV-infected (Lederman et al., 1985; Andes et al., 1989). A more recent survey found 46 percent of 9,496 clotting-factor recipients to be HIV-infected, only 9 of whom had a definitive date of seroconversion subsequent to April 1987 (Fricke et al., 1992). By Dec. 31, 1994, 3,863 individuals in the United States with hemophilia or coagulation disorders had been diagnosed with AIDS (, 1995a). The impact of HIV on the life expectancy of hemophiliacs has been dramatic. In a retrospective study of mortality among 701 hemophilic patients in the United States, median life expectancy for males with hemophilia increased from 40.9 years at the beginning of the century (1900-1920) to a high of 68 years after the introduction of factor therapy (1971 to 1980). In the era of AIDS (1981 to 1990), life expectancy declined to 49 years (Jones and Ratnoff, 1991) (Figure 6). Another analysis found that the death rate for individuals with hemophilia A in the United States rose three-fold between the periods 1979-1981 and 1987-1989. Median age at death decreased from 57 years in 1979-1981 to 40 years in 1987-1989 (Chorba et al., 1994). In the United Kingdom, 6,278 males diagnosed with hemophilia were living during the period 1977-91. During 1979-86, 1,227 were infected with HIV during transfusion therapy. Among 2,448 individuals with severe hemophilia, the annual death rate was stable at 8 per 1,000 during 1977-84; during 1985-92 death rates remained at 8 per 1,000 among HIV-seronegative persons with severe hemophilia but rose steeply in those who were seropositive, reaching 81 per 1,000 in 1991-92. Among 3,830 with mild or moderate hemophilia, the pattern was similar, with an initial death rate of 4 per 1,000 in 1977-84, rising to 85 per 1,000 in 1991-92 among seropositive individuals (Darby et al., 1995). In a British cohort of hemophiliacs infected with HIV between 1979 and 1985 and followed prospectively, 50 of 111 patients had died by the end of 1994, 43 after a diagnosis of AIDS. Only eight of the 61 living patients had CD4+ T cell counts above 500/mm3 (Lee et al., 1995). Newborn infants have no behavioral risk factors, yet 6,209 children in the United States have developed AIDS through Dec. 31, 1994 (, 1995a). Studies have consistently shown that of infants born to HIV-infected mothers, only the 15-40 percent of infants who become HIV-infected before or during birth go on to develop immunosuppression and AIDS, while babies who are not HIV-infected do not develop AIDS (Katz, 1989; d'Arminio et al., 1990; Prober and Gershon, 1991; European Collaborative Study, 1991; Lambert et al., 1990; Lindgren et al. 1991; Andiman et al., 1990; Johnson et al., 1989; Rogers et al., 1989; Hutto et al., 1991). Moreover, in those infants who do acquire HIV and develop AIDS, the rate of disease progression varies directly with the severity of the disease in the mother at the time of delivery (European Collaborative Study, 1992; Blanche et al., 1994). Almost all infants born to seropositive mothers have detectable HIV antibody, which may persist for as long as 15 months. In most cases, the presence of this antibody does not represent actual infection with HIV, but is antibody from the HIV-infected mother that diffuses across the placenta. In a French study of 22 infants born to HIV-infected mothers, seven babies had antibodies to HIV after one year and all developed AIDS. In these seven infants, the presence of HIV antibodies marked actual infection with HIV, not merely antibodies acquired from the mother. The other 15 children showed a complete loss of maternally acquired HIV antibodies, were not actually infected, and remained healthy. Of the babies who developed AIDS, virus was found in four of four infants tested. HIV was not found in the 15 children who remained healthy (Douard et al., 1989; Gallo, 1991). In the European Collaborative Study, children born to HIV-seropositive mothers are followed from birth in 10 European centers. A majority of the mothers have a history of injection drug use. A recent report showed that none of the 343 children who had lost maternally transferred HIV antibodies (i.e. they were truly HIV-negative) had developed AIDS or persistent immune deficiency. In contrast, among 64 children who were truly HIV-infected (i.e. they remained HIV antibody positive), 30 percent presented with AIDS within 6 months of age or with oral candidiasis followed rapidly by the onset of AIDS. By their first birthday, 17 percent died of HIV-related diseases (European Collaborative Study, 1991). In a multicenter study in Bangkok, Thailand, 105 children born to HIV-infected mothers were recently evaluated at 6 months of age (Chearskul et al., 1994). Of 27 infants determined to be HIV-infected by polymerase chain reaction, 24 developed HIV-related symptoms, including six who developed -defined AIDS and four who died with conditions clinically consistent with AIDS. Among 77 exposed but uninfected infants, no deaths occurred. In a study of 481 infants in Haiti, the survival rate at 18 months was 41 percent for HIV-infected infants, 84 percent among uninfected infants born to seropositive women, and 95 percent among infants born to seronegative women (Boulos et al., 1994). Investigators have also reported cases of HIV-infected mothers with twins discordant for HIV-infection in which the HIV-infected child developed AIDS, while the other child remained clinically and immunologically normal (Park et al., 1987; Menez-Bautista et al., 1986; Thomas et al., 1990; Young et al., 1990; Barlow and Mok, 1993; Guerrero Vazquez et al., 1993). Other researchers have used molecular epidemiology to find a single source of HIV for an outbreak of pediatric AIDS cases in Russia. In that country between 1988 and 1990, over 250 children were infected with HIV after exposure to non-sterile needles. By June 1994, 43 of these children had died of AIDS (Irova et al., 1993). In a recent report on 22 of these children from two hospitals, 12 had developed AIDS. Molecular analysis of HIV isolates from all 22 children showed the isolates to be very closely related, confirming epidemiological data that these two outbreaks resulted from a single source: an infant born to an HIV-infected mother whose husband was infected in central Africa (Bobkov et al., 1994). Skeptics of the role of HIV in AIDS have espoused a "risk-AIDS" or a "drug-AIDS" hypothesis (Duesberg, 1987-1994), asserting at different times that factors such as promiscuous homosexual activity; repeated venereal infections and antibiotic treatments; the use of recreational drugs such as nitrite inhalants, cocaine and heroin; immunosuppressive medical procedures; and treatment with the drug AZT are responsible for the epidemic of AIDS. Such arguments have been repeatedly contradicted. Compelling evidence against the risk-AIDS hypothesis has come from cohort studies of high-risk groups in which all individuals with AIDS-related conditions are HIV-antibody positive, while matched, HIV-antibody negative controls do not develop AIDS or immunosuppression, despite engaging in high-risk behaviors. In a prospectively studied cohort in Vancouver (Schechter et al., 1993a), 715 homosexual men were followed for a median of 8.6 years. Among 365 HIV-positive individuals, 136 developed AIDS. No AIDS-defining illnesses occurred among 350 HIV-negative men despite the fact that these men reported appreciable levels of nitrite use, other recreational drug use, and frequent receptive anal intercourse. The average rate of CD4+ T cell decline was 50 cells/mm3 per year in the HIV-positive men, while the HIV-negative men showed no decline. Significantly, the decline of CD4+ T cell counts in HIV-positive men and the stability of CD4+ T cell counts in HIV-negative men were apparent whether or not nitrite inhalants were used. There were 101 AIDS-related deaths among the HIV-seropositive men, including six unrelated to HIV infection. In the seronegative group, only two deaths occurred: one heart attack and one suicide. In this study, lifetime prevalences of risk behaviors were similar in the 136 HIV-seropositive men who developed AIDS and in the 226 HIV-seropositive men who did not develop AIDS: use of nitrite inhalants, 88 percent in both groups; use of other illicit drugs, 75 percent and 80 percent, respectively; more than 25 percent of sexual encounters involving receptive anal intercourse, 78 percent and 82 percent, respectively. Among HIV-seronegative men (none of whom developed AIDS), the lifetime prevalences of these behaviors were somewhat lower, but substantial: 56 percent, 74 percent and 58 percent, respectively. Similar results were reported from the San Francisco Men's Health Study, a cohort of single men recruited in San Francisco in 1984 without regard to sexual preference, lifestyle or serostatus (Ascher et al., 1993a). During 96 months of follow-up, 215 cases of AIDS had occurred among 445 HIV-antibody positive homosexual men, 174 of whom had died. Among 367 antibody-negative homosexual men and 214 antibody-negative heterosexual men, no AIDS cases and eight deaths unrelated to AIDS-defining conditions were observed. The authors found no overall effect of drug consumption, including nitrites, on the development of Kaposi's sarcoma or other AIDS-defining conditions, nor an effect of the extent of the participants' drug use on these conditions. A consistent loss of CD4+ T cells was limited to HIV-positive subjects, among whom there was no discernible difference in CD4+ T cell counts related to drug-taking behavior. Among HIV-seronegative men, moderate or heavy drug users had higher CD4+ T cell counts than non-users. Observational studies of HIV-infected individuals have found that drug use does not accelerate progression to AIDS (Kaslow et al., 1989; Coates et al., 1990; Lifson et al., 1990; Robertson et al., 1990). In a Dutch cohort of HIV-seropositive homosexual men, no significant differences in sexual behavior or use of cannabis, alcohol, tobacco, nitrite inhalants, LSD or amphetamines were found between men who remained asymptomatic for long periods and those who progressed to AIDS (Keet et al., 1994). Another study, of five cohorts of homosexual men for whom dates of seroconversion were well-documented, found no association between HIV disease progression and history of sexually transmitted diseases, number of sexual partners, use of AZT, alcohol, tobacco or recreational drugs (Veugelers et al., 1994). Similarly, in the San Francisco City Clinic Cohort, recruited in the late 1970s and early 1980s in conjunction with hepatitis B studies, no consistent differences in exposure to recreational drugs or sexually transmitted diseases were seen between HIV-infected men who progressed to AIDS and those who remained healthy (Buchbinder et al., 1994). Because many children with AIDS are born to mothers who abuse recreational drugs (Novick and Rubinstein, 1987; European Collaborative Study, 1991), it has been postulated that the mothers' drug consumption is responsible for children developing AIDS (Duesberg, 1987-1994). This theory is contradicted by numerous reports of infants with AIDS born to women infected with HIV through heterosexual contact or transfusions who do not use drugs (, 1995a). As noted above, the only factor that predicts whether a child will develop AIDS is whether he or she is infected with HIV, not maternal drug use. Central to the "risk-AIDS" hypothesis is the notion that chronic injection drug use causes AIDS (Duesberg, 1992), a view that is contradicted by numerous studies. Although some evidence suggests injection drug use can cause certain immunologic abnormalities, such as reduction in natural killer (NK) cell activity (reviewed in Kreek, 1990), the specific immune deficit that leads to AIDS--a progressive reduction of CD4+ T cells resulting in persistent CD4+ T lymphocytopenia--is rare in HIV-seronegative injection drug users in the absence of other immunosuppressive conditions (Des Jarlais et al., 1993; Weiss et al., 1992). In a survey of 229 HIV-seronegative injection drug users in New York City, mean CD4+ T cell counts of the group were consistently over 1000/mm3 (Des Jarlais et al., 1993). Only two individuals had two CD4+ T cell measurements of fewer than 300/mm3, one of whom died with cardiac disease and non-Hodgkin's lymphoma listed as the cause of death. In a study of 180 HIV-seronegative injection drug users in New Jersey, the participants' average CD4+ T cell count was 1169/mm3 (Weiss et al., 1992). Two of these individuals, both with generalized lymphocytopenia, had CD4+ T cell counts less than 300/mm3. In the MACS, median CD4+ T cell counts of 63 HIV-seronegative injection drug users rose from 1061/mm3 to 1124/mm3 in a 15 to 21 month follow-up period (Margolick et al., 1992). In a cross-sectional study, 11 HIV-seronegative, long-term heroin addicts had mean CD4+ T cell counts of 1500/mm3, while 11 healthy controls had CD4+ T cell counts of 820 cells/mm3 (Novick et al., 1989). Recent data also refute the notion that a certain lifetime dosage of injection drugs is sufficient to cause AIDS in HIV-seronegative individuals. In a Dutch study, investigators compared 86 HIV-seronegative individuals who had been injecting drugs for a mean of 7.6 years with 70 HIV-seropositive people who had injected drugs for a mean of 9.1 years. Upon enrollment in 1989, CD4+ T cell counts were 914/mm3 in the HIV-seronegative group, and 395/mm3 in the seropositive group. By 1994, there were 25 deaths attributable to AIDS-defining conditions in the seropositive group; among HIV-seronegative individuals, eight deaths occurred, none due to AIDS-defining diseases (Cohen, 1994a). Excess mortality among HIV-infected injection drug users as compared to HIV-seronegative users has also been observed by other investigators. In a prospective Italian study of 2,431 injection drug users enrolled in drug treatment programs from 1985 to 1991, HIV-seropositive individuals were 4.5 times more likely to die than HIV-seronegative subjects (Zaccarelli et al., 1994). No deaths due to AIDS-defining conditions were seen among 1,661 HIV-seronegative individuals, 41 of whom died of other conditions, predominantly overdose, liver disease and accidents. Among 770 individuals who were HIV-seropositive at study entry or who seroconverted during the study period, 89 died of AIDS-related conditions and 52 of other conditions. In HIV-seropositive individuals, a number of investigators have found no statistical association between injection drug use and decline of CD4+ T cell counts (Galli et al., 1989, 1991; Schoenbaum et al., 1989; Margolick et al., 1992, 1994; Montella et al., 1992; Alcabes et al., 1993b, 1994; Galai et al., 1995), nor a difference in disease progression between active versus former users of injection drugs (Weber et al., 1990; Galli et al., 1991; Montella et al., 1992; Italian Seroconversion Study, 1992). Taken together, these studies suggest that any negative effects of injection drugs on CD4+ T cell levels are limited and may explain why many investigators have found that HIV-seropositive injection drug users have rates of disease progression that are similar to other HIV-infected individuals (Rezza et al., 1990; Montella et al., 1992; Galli et al., 1989; Selwyn et al., 1992; Munoz et al., 1992; Italian Seroconversion Study, 1992; MAP Workshop, 1993; Pezzotti et al., 1992; Margolick et al., 1992, 1994; Alcabes, 1993b, 1994; Galai et al., 1995). It has been asserted "... in America, only promiscuity aided by aphrodisiac and psychoactive drugs, practiced mostly by 20 to 40 year-old male homosexuals and some heterosexuals, seems to correlate with AIDS diseases" (Duesberg, 1991). Even a cursory review of history provides evidence to the contrary: such behaviors have existed for decades --in some cases centuries--and have increased only in a relative sense in recent years, if at all, whereas AIDS clearly is a new phenomenon. If promiscuity were a cause of AIDS, one would have expected cases to have occurred among prostitutes (male or female) prior to 1978. Reports of such cases are lacking, even though prostitution has been present in most if not all cultures throughout history. In this country, trends in gonorrheal infections suggest that extramarital sexual activity was extensive in the pre-AIDS era. Cases of gonorrhea in the United States peaked at approximately 1 million in 1978; between 250,000 and 530,000 cases were reported each year in the 1960s, approximately 250,000 cases each year in the 1950s, and between 175,000 and 380,000 cases annually in the 1940s (, 1987c, 1993b). Despite the frequency of sexually transmitted diseases, only a handful of documented cases of AIDS in the United States prior to 1978 have been reported. Historians, archaeologists and sociologists have documented extensive homosexual activity dating from the ancient Greeks to the well-established homosexual subculture in the United States in the 20th century (Weinberg and Williams, 1974; Gilbert, 1980-81; Saghir and Robins, 1973; Reinisch et al., 1990; Doll et al., 1990; Katz, 1992; Friedman and Downey, 1994). Depictions of anal intercourse, both male and female, can be found in the art and literature of numerous cultures on all inhabited continents (Reinisch et al., 1990). In the 1940s, Kinsey et al. reported that 37 percent of all American males surveyed had at least some overt homosexual experience to the point of orgasm between adolescence and old age and that 10 percent of men were exclusively or predominantly homosexual between the ages of 16 and 55 (Kinsey et al., 1948). More recent surveys have found that 2 to 5 percent of men are homosexual or bisexual (reviewed in Friedman and Downey, 1994; Seidman and Rieder, 1994; Laumann, 1994). Many homosexuals had multiple sexual partners in the pre-AIDS era: a 1969 survey found that more than 40 percent of white homosexual males and one-third of black homosexual males had at least 500 partners in their lifetime, and an additional one-fourth reported between 100 and 500 partners (Bell and Weinberg, 1978). A majority of these men reported that more than half their partners had been strangers before the sexual encounters (Bell and Weinberg, 1978). Further evidence of extensive homosexual behavior in the years preceding the AIDS epidemic comes from reports of numerous cases of rectal gonorrheal and anal herpes simplex virus infections among men (Jefferiss, 1956; Scott and Stone, 1966; Pariser and Marino, 1970; Owen and Hill, 1972; British Cooperative Clinical Group, 1973; Jacobs, 1976; Judson et al., 1977; Merino and Richards, 1977; McMillan and Young, 1978). A temporal association between the onset of extensive use of recreational drugs and the AIDS epidemic is also lacking. The widespread use of opiates in the United States has existed since the middle of the 19th century (Courtwright, 1982); as many as 313,000 Americans were addicted to opium and morphine prior to 1914. Heroin use spread throughout the country in the 1920s and 1930s (Courtwright, 1982), and the total number of active heroin users peaked at about 626,000 in 1971 (Greene et al., 1975; Friedland, 1989). Opiates were initially administered by oral or inhalation routes, but by the 1920s addicts began to inject heroin directly into their veins (Courtwright, 1982). In 1940, intravenous use of opiates was seen in 80 percent of men admitted to a large addiction research center in Kentucky (Friedland, 1989). While cocaine use increased markedly during the 1970s (Kozel and Adams, 1986), the use of the drug, frequently with morphine, is well-documented in the United States since the late 19th century (Dale, 1903; Ashley, 1975; Spotts and Shontz, 1980). For example, a survey in 1902 reported that only 3 to 8 percent of the cocaine sold in New York, Boston and other cities went into the practice of medicine or dentistry (Spotts and Shontz). After a period of relative obscurity, cocaine became increasingly popular in the late 1950s and 1960s. Over 70 percent of 1,100 addicts at the addiction research center in Kentucky in 1968 and 1969 reported use or abuse of cocaine (Chambers, 1974). The recreational use of nitrite inhalants ("poppers") also predates the AIDS epidemic. Reports of the widespread use of these drugs by young men in the 1960s were the impetus for the reinstatement by of the prescription requirement for amyl nitrite in 1968 (Israelstam et al., 1978; Haverkos and Dougherty, 1988). Since the early years of the AIDS epidemic, the use of nitrite inhalants has declined dramatically among homosexual men, yet the number of AIDS cases continues to increase (Ostrow et al., 1990, 1993; Lau et al., 1992). In the general population, the number of individuals aged 25 to 44 years reporting current use of marijuana, cocaine, inhalants, hallucinogens and cigarettes declined between 1974 and 1992, while the AIDS epidemic worsened (Substance Abuse and Mental Health Services Administration, 1994). Although some individuals maintain that treatment with zidovudine (AZT) has compounded the AIDS epidemic (Duesberg, 1992), published reports of both placebo-controlled clinical trials and observational studies provide data to the contrary (Table 4). El ensayo Concorde y 298 VA en comparación inmediata (IMM) y diferidos (DEF) el uso de zidovudina (ZDV), la zidovudina otros ensayos compararon (ZDV) y placebo (P) .; ??? Or p24 antigenemia.; ??? In ACTG 019, original treatment group included placebo, 500 mg. ZDV / día o 1.500 mg. ZDV / día .; ?? Después de la apertura del ciego del ensayo aleatorio original, en 1989, los sujetos en cada brazo original, se les ofreció una dosis diaria de 500 mg. De etiqueta abierta zidovudina .; Modificado de Comité de Coordinación Concorde de 1994. En los pacientes con enfermedad sintomática por el VIH, para los cuales se mide un efecto beneficioso en meses, el AZT parece ralentizar la progresión de la enfermedad y prolongar la vida, de acuerdo a doble ciego, los estudios clínicos controlados con placebo (revisado en Sande et al, 1993;. McLeod y Hammer, 1992; Volberding y Graham, 1994). Un ensayo clínico conocido como BW 002 comparó AZT con placebo en 282 pacientes con SIDA o con signos o síntomas de la enfermedad por VIH avanzada. In this study, which led to the approval of AZT by theernment, only one of 145 patients treated with AZT died compared with 19 of 137 placebo recipients in a six month period. Las infecciones oportunistas se produjeron en 24 receptores de AZT y 45 recibieron placebo. Además de reducir la mortalidad, AZT se demostró que han reducido la frecuencia y gravedad de las infecciones oportunistas asociadas con el SIDA, la mejora de peso corporal, deterioro impedido en la puntuación de rendimiento de Karnofsky, y el aumento de los recuentos de linfocitos T CD4 + en la sangre periférica (Fischl et al. , 1987;. Richman et al, 1987). Seguimiento continuo de 229 de estos pacientes mostró que el beneficio en la supervivencia del AZT extendido a por lo menos 21 meses después del inicio de la terapia; supervivencia en el grupo de tratamiento original fue de 57,6 por ciento en ese momento, mientras que la supervivencia entre los miembros del grupo original de placebo fue del 51,5 por ciento en nueve meses (Richman y Andrews, 1988;. Fischl et al, 1989). En otro estudio controlado con placebo, conocido como ACTG 016, en el que participaron 711 pacientes infectados por el VIH sintomáticos con recuentos de células T CD4 + entre 200 y 500 células / mm3, los que tomaban AZT eran menos propensos a experimentar progresión de la enfermedad que aquellos que recibieron placebo durante un estudio de la mediana período de 11 meses (Fischl et al., 1990). En este estudio, no hubo diferencia en la progresión de la enfermedad se observó entre los participantes que comenzaron el ensayo con células T CD4 + que cuenta mayor de 500 / mm3. estudio de la Administración de Veteranos de 338 individuos con síntomas tempranos de la enfermedad del VIH y recuentos de células T CD4 + entre 200 y 500 células / mm3 encontró que la terapia inmediata retrasa significativamente la progresión de la enfermedad en comparación con el tratamiento diferido, pero no alargar (o acortar) la supervivencia después de un promedio período de estudio de más de dos años (Hamilton et al., 1992). Entre los individuos infectados por el VIH asintomáticos, varios ensayos clínicos controlados por placebo sugieren que el AZT puede retrasar la progresión de la enfermedad durante 12 a 24 meses, pero en última instancia no aumentar la supervivencia. De manera significativa, a largo plazo de seguimiento de personas que participan en estos ensayos, aunque no muestran un beneficio prolongado de AZT, nunca ha indicado que el fármaco aumenta la progresión de la enfermedad o mortalidad (revisado en McLeod y Hammer, 1992;. Sande et al, 1993; Volberding y Graham, 1994). La falta de casos de SIDA en exceso y la muerte en los brazos de AZT de estos grandes ensayos refuta de manera efectiva el argumento de que el AZT causa el SIDA. Durante un período de seguimiento de 4,5 años (media 2,6 años) de un ensayo conocido como ACTG 019, no se observaron diferencias en la supervivencia global entre los grupos de AZT y de placebo entre 1.565 pacientes asintomáticos que entran en el estudio con menos de 500 células T CD4 + / mm3 ( Volberding et al., 1994). En ese estudio, el AZT fue superior al placebo en el retraso de la progresión a SIDA o ARC avanzada durante aproximadamente un año, y un beneficio más prolongada se observó entre un subgrupo de pacientes. El estudio Concorde en Europa inscrito 1.749 pacientes asintomáticos con células T CD4 + inferior a 500 / mm3. En ese estudio, no se observaron diferencias estadísticamente significativas en la progresión a enfermedad avanzada después de tres años entre los individuos que tomaban AZT inmediatamente y los que aplazarse la terapia con AZT o no tomaron el fármaco (Comité de Coordinación de la Concordia, 1994). Sin embargo, la tasa de progresión a la muerte, el SIDA o ARC grave fue más lenta en el grupo de AZT "inmediata" durante el primer año de tratamiento. Aunque el estudio Concorde no mostró un beneficio significativo en el tiempo con el uso temprano de AZT, se demostró claramente que el AZT no era perjudicial para los pacientes en el grupo de AZT "inmediato" en comparación con el grupo de AZT "diferido". Un estudio europeo-australiano (EACG 020) de 993 pacientes con células T CD4 + superior a 400 / mm3 no mostró diferencias entre AZT y brazos de placebo del ensayo durante un periodo de estudio mediana de 94 semanas, aunque AZT hizo retrasar la progresión a cierta clínica y los puntos finales inmunológicos para un máximo de tres años (Cooper et al., 1993). Tanto este estudio y el estudio Concorde informaron poco severa toxicidad hematológica relacionada con AZT en dosis de 1000 mg / día, que es el doble de la dosis diaria recomendada en los Estados Unidos. Los estudios no controlados han encontrado aumento de la supervivencia y / o la frecuencia de las infecciones oportunistas reducida en pacientes con la enfermedad del VIH y el SIDA que fueron tratados con AZT u otros anti-retrovirales (Creagh-Kirk et al, 1988;.. Moore et al, 1991a, b; Ragni et al, 1992;.. Schinaia et al, 1991;. Koblin et al, 1992;. Graham et al, 1991, 1992, 1993; Longini, 1993;. Vella et al, 1992, 1994;. Saah et al, 1994;. Bacellar et al, 1994). In the Multicenter AIDS Cohort Study, for example, HIV-infected individuals treated with AZT had significantly reduced mortality and progression to AIDS for follow-up intervals of six, 12, 18 and 24 months compared to those not taking AZT, even after adjusting for health status, CD4+ T cell counts and PCP prophylaxis (Graham et al., 1991, 1992). Además, varios estudios de cohortes muestran que la esperanza de vida de las personas con SIDA ha aumentado desde el uso de AZT se hizo común en 1986-87. Among 362 homosexual men in hepatitis B vaccine trial cohorts in New York City, San Francisco and Amsterdam, the time from seroconversion to death, a period not influenced by variations in diagnosing AIDS, has lengthened slightly in recent years (Hessol et al., 1994). En un estudio holandés de 975 hombres y mujeres con infección por VIH, la supervivencia media de SIDA aumentó de nueve meses en el período 1982-1985 a 26 meses en 1990 (Bindels et al., 1994). Incluso teniendo en cuenta los beneficios de la mejora de la profilaxis y el tratamiento de PCP, si el AZT o estaban contribuyendo a que causa la enfermedad, se podría esperar una disminución en las cifras de supervivencia, en lugar de un aumento paralelo al uso de AZT. En un análisis del Estudio de Salud de los Hombres San Francisco, los investigadores señalan que 169 (73 por ciento) de 233 pacientes con SIDA había sido tratado con AZT en un momento u otro. Sin embargo, 90 (el 53 por ciento de la 169) fueron diagnosticados con SIDA clínico antes de comenzar el tratamiento con AZT y otros 51 (30 por ciento de las 169) tenían recuentos de células T CD4 + inferiores a 200 / mm3 antes del inicio del tratamiento con AZT (Ascher et al. , 1995). Los autores concluyen: "Estos datos no son consistentes con la hipótesis de un papel causal de AZT en el SIDA." It has been argued that HIV cannot cause AIDS because the body develops HIV-specific antibodies following primary infection (Duesberg, 1992). This reasoning ignores numerous examples of viruses other than HIV that can be pathogenic after evidence of immunity appears (Oldstone, 1989). Primary poliovirus infection is a classic example of a disease in which high titers of neutralizing antibodies develop in all infected individuals, yet a small percentage of individuals develop subsequent paralysis (Kurth, 1990). Measles virus may persist for years in brain cells, eventually causing a chronic neurological disease despite the presence of antibodies (Gershon, 1990). Viruses such as cytomegalovirus, herpes simplex and varicella zoster may be activated after years of latency even in the presence of abundant antibodies (Weiss and Jaffe, 1990). Lentiviruses with long and variable latency periods, such as visna virus in sheep, cause central nervous system damage even after the specific production of neutralizing antibodies (Haase, 1990). Furthermore, it is now well-documented that HIV can mutate rapidly to circumvent immunologic control of its replication. It has been argued that AIDS among transfusion recipients is due to underlying diseases that necessitated the transfusion, rather than to HIV (Duesberg, 1991). This theory is contradicted by a report by the Transfusion Safety Study Group, which compared HIV-negative and HIV-positive blood recipients who had been given transfusions for similar diseases. Approximately three years after the transfusion, the mean CD4+ T cell count in 64 HIV-negative recipients was 850/mm3, while 111 HIV-seropositive individuals had average CD4+ T cell counts of 375/mm3 (Donegan et al., 1990). By 1993, there were 37 cases of AIDS in the HIV-infected group, but not a single AIDS-defining illness in the HIV-seronegative transfusion recipients (Cohen, 1994d). People have received blood transfusions for decades; however, as discussed above, AIDS-like symptoms were extraordinarily rare before the appearance of HIV. Recent surveys have shown that AIDS-like symptoms remain very rare among transfusion recipients who are HIV-seronegative and their sexual contacts. In one study of transfusion safety, no AIDS-defining illnesses were seen among 807 HIV-negative recipients of blood or blood products, or 947 long-term sexual or household contacts of these individuals (Aledort et al., 1993). In addition, through 1994, the had received reports of 628 cases of AIDS in individuals whose primary risk factor was sex with an HIV-infected transfusion recipient (, 1995a), a finding not explainable by the "risk-AIDS" hypothesis. It has also been argued that cumulative exposure to foreign proteins in Factor VIII concentrates leads to CD4+ T cell depletion and AIDS in hemophiliacs (Duesberg, 1992). This view is contradicted by several large studies. Among HIV-seronegative patients with hemophilia A enrolled in the Transfusion Safety Study, no significant differences in CD4+ T cell counts were noted between 79 patients with no or minimal factor treatment and 53 patients with the largest amount of lifetime treatments (cumulative totals in the latter group ranged from 100,000 to 2,000,000 U in two years) (Hassett et al., 1993). Although the CD4+ T cell counts seen in the low- and high- groups (756/mm3 and 718/mm3, respectively) were 20 to 25 percent lower than controls, such levels are still within the normal range. Geographic Considerations In a report from the Multicenter Hemophilia Cohort Study, the mean CD4+ T cell counts among 161 HIV-seronegative hemophiliacs was 784/mm3; among 715 HIV-seropositive hemophiliacs, the mean CD4+ T cell count was 253/mm3 (Lederman et al., 1995). In another study, no instances of AIDS-defining illnesses were seen among 402 HIV-seronegative hemophiliacs treated with factor therapy or in 83 hemophiliacs who received no treatment subsequent to 1979 (Aledort et al., 1993; Mosely et al., 1993). In a retrospective study of patients with severe hemophilia A, the rate of CD4+ T cell loss was 31.4 every six months for 41 HIV-seropositive individuals without AIDS and 49.7 every six months for 14 HIV-seropositive individuals with AIDS. In contrast, among 28 HIV-seronegative individuals, CD4+ T cell counts increased at a rate of 13.1 cells/six months (Becherer et al., 1990). In a study of children and adolescents with hemophilia, the median CD4+ T cell count of 126 HIV-seronegative individuals was 895/mm3 at study entry; no individuals had CD4+ T cell counts below 200/mm3. In contrast, 26 percent of seropositive children had CD4+ T cell counts of less than 200/mm3; the mean CD4+ T cell count for seropositive children was 423/mm3 (Jason et al., 1994). Although some reports have suggested that high-purity Factor VIII concentrates are associated with a slower rate of CD4+ T cell decline in HIV-infected hemophiliacs than products of low and intermediate purity (Hilgartner et al., 1993; Goldsmith et al., 1991; de Biasi et al., 1991), other studies have shown no such benefit (Mannucci et al., 1992; Gjerset et al., 1994). In a study of 525 HIV-infected hemophiliacs, Transfusion Safety Study investigators found that neither the purity nor the amount of Factor VIII therapy had a deleterious effect on CD4+ T cell counts (Gjerset et al., 1994). Similarly, the Multicenter Hemophilia Cohort Study found no association between the cumulative dose of plasma concentrate and incidence of AIDS among 242 HIV-infected hemophiliacs and thus "no support for cofactor hypotheses involving either antigen stimulation or inoculum size" (Goedert et al., 1989). In addition to the evidence from the cohort studies cited above, it should be noted that 10 to 20 percent of wives and sex partners of male HIV-positive hemophiliacs in the United States are also HIV-infected (Pitchenik et al., 1984; Kreiss et al., 1985; Peterman et al., 1988; Smiley et al., 1988; Dietrich and Boone, 1990; Lusher et al., 1991). Through December 1994, the had received reports of 266 cases of AIDS in those who had sex with a person with hemophilia (, 1995a). These data cannot be explained by a non-infectious theory of AIDS etiology. Certain skeptics maintain that the distribution of AIDS cases casts doubt on HIV as the cause of the syndrome. They claim infectious microbes are not gender-specific, yet relatively few people with AIDS are women (Duesberg, 1992). In fact, the distribution of AIDS cases, whether in the United States or elsewhere in the world, invariably mirrors the prevalence of HIV in a population (U.S. Bureau of the Census, 1994). In the United States, HIV first appeared in populations of homosexual men and injection drug users, a majority of whom are male (Curran et al., 1988). Because HIV is spread primarily through sex or by the exchange of HIV-contaminated needles during injection drug use, it is not surprising that a majority of U.S. AIDS cases have occurred in men. Increasingly, however, women are becoming HIV-infected, usually through the exchange of HIV-contaminated needles or sex with an HIV-infected male (Vermund, 1993b; , 1995a). As the number of HIV-infected women has risen, so too have the number of female AIDS cases. In the United States, the proportion of AIDS cases among women has increased from 7 percent in 1985 to 18 percent in 1994. AIDS is now the fourth leading cause of death among women aged 25 to 44 in the United States (, 1994). Evidence From Blood Donor-Recipient Pairs In Africa, HIV was first recognized in sexually active heterosexuals, and in some parts of Africa AIDS cases have occurred as frequently in women as in men (Quinn et al., 1986; Mann, 1992a). In Zambia, for example, the 29,734 AIDS cases reported to the WHO through October 20, 1993, were equally divided among males and females (WHO, 1995a,b). One vocal skeptic of the role of HIV in AIDS argues that, in Africa, AIDS is nothing more than a new name for old diseases (Duesberg, 1991). It is true that the diseases that have come to be associated with AIDS in Africa--wasting, diarrheal diseases and TB--have long been severe burdens there. However, high rates of mortality from these diseases, formerly confined to the elderly and malnourished, are now common among HIV-infected young and middle-aged people (Essex, 1994). In a recent study of more than 9,000 individuals in rural Uganda, people testing positive for HIV antibodies were 60 times as likely to die during the subsequent two-year observation period as were otherwise similar persons who tested negative (Mulder et al., 1994b). Large differences in mortality were also seen between HIV-seropositive and HIV-seronegative individuals in another large Ugandan cohort (Sewankambo et al., 1994). Elsewhere in Africa findings are similar. One study of 1,400 Rwandan women tested for HIV during pregnancy found that HIV infected women were 20 times more likely to die in the two years following pregnancy than their HIV-negative counterparts (Lindan et al., 1992). In another study in Rwanda, 215 HIV-seropositive women and 216 HIV-seronegative women were followed prospectively for up to four years, during which time 21 women developed AIDS (WHO definition), all of them in the HIV-seropositive group. The mortality rate among the HIV-seropositive women was nine times higher than seen among the HIV-seronegative women (Leroy et al., 1995) In Zaire, investigators found that families in which the mother was HIV-1 seropositive experienced a five- to 10-fold higher maternal, paternal and early childhood mortality rate than families in which the mother was HIV-seronegative (Ryder et al., 1994b). In another study in Zaire, infants with HIV infection were shown to have an 11-fold increased risk of death from diarrhea compared with uninfected children (Thea et al., 1993). In patients with pulmonary tuberculosis in Cote d'Ivoire, HIV-seropositive individuals were 17 times more likely to die than HIV-seronegative individuals (Ackah et al., 1995). The extraordinary death rates among HIV-infected individuals confirm that the virus is an important cause of premature mortality in Africa (Dondero and Curran, 1994). HIV and AIDS have been repeatedly linked in time, place and population group; the appearance of HIV in the blood supply has preceded or coincided with the occurrence of AIDS cases in every country and region where AIDS has been noted. Among individuals without HIV, AIDS-like symptoms are extraordinarily rare, even in populations with many AIDS cases. Individuals as different as homosexual men, elderly transfusion recipients, heterosexual women, drug-using heterosexual men and infants have all developed AIDS with only one common denominator: infection with HIV. Laboratory workers accidentally exposed to highly concentrated HIV and health care workers exposed to HIV-infected blood have developed immunosuppression and AIDS with no other risk factor for immune dysfunction. Scientists have now used PCR to find HIV in virtually every patient with AIDS and to show that HIV is present in large and increasing amounts even in the pre-AIDS stages of HIV disease. Researchers also have demonstrated a correlation between the amount of HIV in the body and progression of the aberrant immunologic processes seen in people with AIDS. Despite this plethora of evidence, the notion that HIV does not cause AIDS continues to find a wide audience in the popular press, with potential negative impact on HIV-infected individuals and on public health efforts to control the epidemic. HIV-infected individuals may be convinced to forego anti-HIV treatments that can forestall the onset of the serious infections and malignancies of AIDS (Edelman et al., 1991). Pregnant HIV-infected women may dismiss the option of taking AZT, which can reduce the likelihood of transmission of HIV from mother to infant (Connor et al., 1994; Boyer et al., 1994). 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