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

a) Why primates, experimentally exposed to low doses of SIV or preexposed to genetically related non-pathogenic SIV, develop resistance to high doses of the pathogenic SIVs (38-43, 91-95); b) why thousands of health care workers exposed to HIV-1-infected body fluids are still seronegative (10-12); c) why there is clear-cut separation of pediatric patients, one group that progresses rapidly to AIDS within a year after birth and the other group which apparently clear HIV-1 from their system (30); d) why patients or primates infected with nef--negative or nef-defective virus have done well (88, 93, 128); e) why there is so much variability in the susceptibility of PBMCs infected with HIV-1, in vitro (122-124), f) why some men with many different partners with whom they practiced receptive anal intercourse have remained seronegative, despite repeated exposure (1-3, 80-82, 117); g) why HTLV-II has been shown to be endemic in certain native American Indians without manifestation of clinical disease (110) and why infection with HTLV-I in the majority of individuals leads to no adverse consequences but causes diseases, (either adult T-cell leukemia if acquired in infancy, or a chronic neuropathic disease if acquired late in life), in very small minority and in individuals whose "molecular immunity" is not fully active (110); h) why all the primates infected with various strains of SlVagm in the wild exhibit no clinical signs of AIDS or other related illnesses (96-100), but if exposed to different strains (to which they were previously unexposed) get sick (100-107). The explanation of this manifestation, if we accept the two dose hypothesis, is that primates get exposed to doses of SIVs in utero or during nursing period, making them immune to that particular strain or related strain of SIVs, but when experimentally exposed to genetically different strain of SIVs (which is almost always with high doses of SIVs) they get sick.

We would also suggest that any agent(s) which induces certain dysfunctions in CD8+ lymphocytes may lead to non-specific activation of the immune system. Also, any agent(s) which non-specifically stimulates T-lymphocytes (i.e. T-cell mitogens PHA, ConA, anti CD3/CD28, IL-2 etc.) could induce alterations in the anti-retroviral immune mechanisms. Several experiments by various investigators have provided information regarding these events. Zack et al. (129) evaluated the molecular events after HIV-1 entry into CD4+ lymphocytes and after entry into unstimulated human PBMC. They showed that the HIV-1 genome is blocked from completing reverse transcription by some unknown host factor(s). Even though viral RNA and incomplete reverse transcripts of proviral DNA may persist for a short period of time, they are labile and are degraded by host factor(s). Stimulation of PBMC with a T-lymphocyte mitogen results in the breakdown of this natural defense system against HIV-1. More recently, Best et al (130) have identified a gene, Fv1, an endogenous Gag-related gene found in certain strains of mice, which makes them resistant to murine leukemia virus. The Fv1 gene product, is able to block virus in the early phase of the viral life cycle. The course of infection is blocked after RT, but before the establishment of the integrated provirus in the host genome. The location of anti-retroviral action of Fv1 (cytoplasm or nucleus) is still undetermined (130). In a different series of experiments, Bukrinsky et al. (131) have examined the PBMC from HIV-1-seropositive individuals, for the presence of HIV-1 provirus. In their studies, they observed that in the resting (quiescent) T cells from asymptomatic individuals, HIV-1 existed as unintegrated full-length HIV-1 but not as an integrated form. This observation suggests that certain naturally occurring host factors may be preventing the integration of HIV-1 provirus. However, when the PBMC were activated with mitogen in vitro, HIV-1 provirus integrated into the host genome. The same authors further noticed that in AIDS patients, the percentage of integrated HIV-1 was higher and was associated with HLA-DR-positive T cells (activated subsets of T cells). Recently, Sonza et ai (116) have shown that in fresh PBMC-monocytes also, HIV-1 replication is blocked prior to RT and integration steps. Therefore, there is evidence of natural defense against HIV-1 at pre-reverse transcription stages, as well as pre-integration stages.

In summary, there is growing evidence that neither the humoral immune responses nor the traditionally understood viral-specific CTL appear to play any important role in the inhibition of HIV-1 replication in vivo. The majority of the HIV-1 vaccine strategies that have received the greatest attention to date, including the use of recombinant HIV-1-envelop glycoprotein immunogens, live vaccinia virus subunits and many vaccine approaches to elicit virus-specific CTL have given disappointing results. We believe that the real natural defenses against HIV-1 lies inside the CD8+ T-cells and understanding the mechanisms by which these intracellular "molecular immunity" pathways operate would provide us the tools we need to fight against HIV-1.