Received 6/18/97, Accepted 7/22/97

Even though a vast majority of human with high risk behaviors, exposed to HIV-1 become infected, some individuals remain uninfected with the virus, despite histories of multiple high-risk sexual exposure to the virus (1-3). For example, it had been shown that the CD4+ T-cells of some individuals resisted very high doses of virus (about 1000-fold more virus to than what was required to establish infection). Also, in these individuals, the majority of cells failed to support viral replication (4). Recently, it was shown that three chemokines, MIP-1 alpha, MIP-1 beta and RANTES suppress HIV-1 ability to infect CD4+ lymphocytes (5) and, more recently, that the cellular receptors through which these chemicals exert their effect- the coreceptors CCR5 and CXCR4 (6-7). Intense genetic analyses of the CCR5 coreceptors have revealed that certain individuals (about 1%) have a 32-base pair deletion allele, CCR5D³². The individuals who posses homozygous defect in CCR5 are resistant to monocyte-tropic strains of HIV-1 (8-9). It have also been documented that about 11-17% of Caucasians and 0-1.7% of African Americans are heterozygous for this CCR5D³². But it appears that presence of only 1 deleted CCR5 does not protect the individuals from HIV-1 infection (4, 8-9), but there is an indication that it may slow down the progression of AIDS (8-9). However, these observation do not explain the fact that why the majority of health care workers who got exposed to HIV-1 did not become infected with the virus? There are over 2084 health care workers in the U.S. who were accidentally exposed to HIV-1 and were monitored by the Center for disease control CDC, only 4 individuals who have no other source of exposure did become seropositive (10-12). Furthermore, several investigators have reported isolation of HIV-1 from individuals who remained HIV-1-seronegative and free of disease (13-16).

The central role of CD8+ T-cells and their anti-retroviral-factor(s) (CAF) has been well documented (17-24). CAF from healthy HIV-1-infected or uninfected individuals can suppress HIV-1 replication without killing the infected cells. These are non-CTL, noncytolytic, non-MHC restricted CD8+ T-cells, characterized by their ability to reduce HIV-1-replication. We wish to present an abundance of previously-published data, including our own, to support the hypothesis that CAF belongs to an unique form of natural immunity, distinct from cell-mediated (CMI) and humoral arms of immunity (HI). We also wish to show how several substances of abuse may adversely affect the anti-retrovirus effects of CD8+ T-cells. The mechanisms by which CD8+ T-cells inhibit retroviral replication are poorly defined.