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Six morphine-dependent and 3 control male Indian rhesus macaques were intravenously inoculated with mixture of SHIVKU, SHIV89.6P and SIV/17E-Fr. These animals were followed for a period of 56 weeks for virus replication, disease progression and immune responses. Both morphinedependent and control macaques showed precipitous loss of CD4+ T cells but CD4 recovery was found to better in more control animals than that in the morphine-dependent animals. The plasma and CSF viral load was significantly higher in morphine-dependent group than those in the control group. Four morphine-dependent succumbed to SIV/SHIV-induced AIDS at week 18, 19, 20 and 51, post-infection with neurological disorders in 3 of those 4 animals. Other 2 morphine-dependent and 3 controls were still alive at the end of 56 week observation period. All 3 viruses replicated in the blood of both morphinedependent and control macaques, but cerebral compartment showed a selection phenomenon and only SIV/17EFr and SHIVKU crossed the blood brain barrier (BBB). The morphine-dependent macaques further favored the viral migration through blood brain barrier (BBB). Three morphine-dependent macaques (euthanized at weeks 18, 19 and 20) did not develop cellular or humoral immune responses whereas other 3 morphine-dependent and 3 control macaques developed both cellular and humoral immune responses. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Pathogenic SIV infections of non-human primates (such as rhesus macaques [RMs]) and HIV infections of humans are characterized by progressive CD4 T cell depletion and dysfunction in association with high levels of virus replication and generalized immune activation. In marked contrast, non-pathogenic infections of non-human primate species that are natural hosts for SIV infection, such as sooty mangabeys (SMs), are characterized by the numerical and functional preservation of CD4 T cell populations and the absence of aberrant immune activation despite levels of virus replication that equal or exceed those commonly found in pathogenic SIV and HIV infections. In light of these observations, it appears that chronic generalized immune activation and its associated immunopathology are more important drivers of progression to AIDS than the direct cytopathic consequences of virus infection. To better understand the cellular and molecular bases of whether or not chronic immune activation and attendant immunopathology follow CD4+ T cell tropic lentivirus infection, we studied how and when host innate and adaptive immune responses diverge following SIV infection of SMs and RMs, and compared these results with those obtained in studies of HIV-infected humans. Interestingly, differences in innate immune responses (eg, dendritic cell activation and migration) to infection are evident from the first days of infection, which are then followed by substantive differences in the magnitude and nature of adaptive immune responses. These differences in in vivo behavior of dendritic cells are recapitulated following ex vivo exposure of SM, RM and human plasmacytoid dendritic cells to specific TLR ligands and to inactivated virus. In contrast to pDCs from RMs and humans, pDCs from SMs fail to produce IFN-alpha following exposure to specific TLR ligands and to SIV – apparently the result of divergent propagation of activation signals along post-receptor pathways. At the organismal level, gene expression profiling studies further indicate that a major feature distinguishing pathogenic from non-pathogenic CD4+ T cell tropic lentivirus infections is the extent to which a pattern of type 1 interferon production and response profiles are manifest. In all, our results indicate that natural host species, such as SMs, may avoid AIDS by the genetically programmed failure of their innate immune systems to respond to the presence of virus in a way that initiates and maintains a state of generalized and deleterious immune activation.

Background The ability of emerging pathogens to infect new species is likely related to the diversity of pathogen variants present in existing reservoirs and their degree of genomic plasticity, which determines their ability to adapt to new environments. Certain simian immunodeficiency viruses (SIVcpz, SIVsm) have demonstrated tremendous success in infecting new species, including humans, resulting in the HIV-1 and HIV-2 epidemics. Although SIV diversification has been studied on a population level, the essential substrates for cross-species transmission, namely SIV sequence diversity and the types and extent of viral diversification present in individual reservoir animals have not been elucidated. To characterize this intra-host SIV diversity, we performed sequence analyses of clonal viral envelope (env) V1V2 and gag p27 variants present in individual SIVsm-infected sooty mangabeys over time. Results SIVsm demonstrated extensive intra-animal V1V2 length variation and amino acid diversity (le38%), and continual variation in V1V2 N-linked glycosylation consensus sequence frequency and location. Positive selection was the predominant evolutionary force. Temporal sequence shifts suggested continual selection, likely due to evolving antibody responses. In contrast, gag p27 was predominantly under purifying selection. SIVsm V1V2 sequence diversification is at least as great as that in HIV-1 infected humans, indicating that extensive viral diversification in and of itself does not inevitably lead to AIDS. Conclusion Positive diversifying selection in this natural reservoir host is the engine that has driven the evolution of the uniquely adaptable SIV/HIV envelope protein. These studies emphasize the importance of retroviral diversification within individual host reservoir animals as a critical substrate in facilitating cross-species transmission.