In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4 ؉ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts IntroductionIt is now clear that human immunodeficiency virus type 1 (HIV-1) evolved from a closely related virus of chimpanzees (Pan troglodytes) named simian immunodeficiency virus (SIVcpz). [1][2][3] Similarly, HIV-2 originated from a related virus, SIVsmm, which naturally infects sooty mangabeys (SMs). [4][5][6] In marked contrast to HIV infection, which almost invariably progresses to AIDS unless treated with antiretrovirals, natural SIVcpz infection of chimpanzees and SIVsmm infection in SMs rarely result in clinical symptoms. [7][8][9][10][11][12] Similarly, other natural hosts for SIV, such as African green monkeys (AGMs), mandrills, and several other African nonhuman primate (NHP) species, generally live normal lifespans despite many years of infection with a highly replicating virus. [13][14][15][16][17][18][19][20][21][22][23] Importantly, the inoculation of SIV, which naturally infects African monkeys, into NHPs that are not natural hosts for SIV, such as macaques and baboons, may result in chronic infection that eventually progresses to a disease closely resembling AIDS. 16,[24][25][26][27][28] Given that the earliest documented exposure of a human to HIV-1 infection was in 1959, 29 it is thought that the introduction of primate lentiviruses into a new host species results in AIDS because of the inability of a naive immune system to cope with a virus recently transmitted from another species. Although it is agreed that the rarity of disease likely reflects a pacific coevolution between SIV and its natural hosts resulting from many thousands of years of endemic infection, the exact mechanisms underlying this absence of disease are still poorly understood. It should be noted, however, that the preservation of the immune system in natural SIV hosts does not simply result from immune control of viral replication, a task obviously not achieved in these animals given their high level of viral load (VL). 7,8,12,14,[19][20][21][22][23] In addition, the differences in virulence between the SIVs naturally infecting African NHP hosts and the pathogenic HIV/SIV strains are not related to differences in virus biology. As do most HIV/SIVmac/ SIVsmm strains, SIVs from African species use CD4 as a receptor 30 and CCR5 as a major coreceptor ...

Background Alcohol use disorders (AUD) are a frequent comorbidity in a large percentage of people living with HIV/AIDS (PLWHA). PLWHA with comorbid AUDs are consistently found to perform poorly at most levels of the HIV treatment cascade, resulting in a higher likelihood of virologic non-suppression. This has been partly attributed to lower rates of persistence with and adherence to antiretroviral therapies (ART). Focus groups of in-care PLWHA identify the need to suspend ART on drinking days because of the potential for toxicity and/or lack of therapeutic effectiveness. The aim of this study was to examine whether chronic binge alcohol (CBA) consumption decreases the effectiveness of uninterrupted ART, specifically that of nucleoside reverse transcriptase inhibitors (NRTI) tenofovir and emtricitabine in suppressing viral replication, or results in drug toxicity in simian immunodeficiency virus (SIV) infected rhesus macaques. Methods Daily CBA or isocaloric sucrose (SUC) administration was initiated three months prior to intrarectal SIVmac251 inoculation and continued throughout the study period. ART was initiated 2.5 months after SIV infection and continued through the study period. Results CBA administration did not prevent or delay the ART-mediated reduction in viral load. Following ART, circulating levels of total protein and creatinine were significantly higher than baseline values in both sucrose- and alcohol-treated animals, but still within a normal range. No evidence of ART toxicity was observed in either CBA- or SUC-administered macaques. Conclusions These findings indicate that CBA does not attenuate effectiveness of NRTI suppression of viral load, nor does it appear to interact with NRTI to produce toxicity during the initial 2 months of treatment. We conclude that while efforts to reduce AUD in PLWHA should be a priority, and that counseling on the importance of adherence to ART even on drinking days should also be promoted.

Induction of virus-specific T-cell responses in mucosal as well as systemic compartments of the immune system is likely to be a critical feature of an effective AIDS vaccine. We investigated whether virus-specific CD8 ؉ lymphocytes induced in rhesus macaques by immunization with attenuated simian immunodeficiency virus (SIV), an approach that is highly effective in eliciting protection against mucosal challenge, express the mucosa-homing receptor ␣4␤7 and traffic to the intestinal mucosa. SIV-specific CD8 ؉ T cells expressing ␣4␤7 were detected in peripheral blood and intestine of macaques infected with attenuated SIV. In contrast, virusspecific T cells in blood of animals immunized cutaneously by a combined DNA-modified vaccinia virus Ankara regimen did not express ␣4␤7. These results demonstrate the selective induction of SIV-specific CD8 ؉ T lymphocytes expressing ␣4␤7 by a vaccine approach that replicates in mucosal tissue and suggest that induction of virus-specific lymphocytes that are able to home to mucosal sites may be an important characteristic of a successful AIDS vaccine.

In this study in Rhesus macaques, we tested whether IL-12 or IL-15 in a DNA prime-oral Listeria boost amplifies the SIV-Gag-specific CD8 mucosal response. SIV-specific CD8 T cells were demonstrated in the peripheral blood (PB) in all test vaccine groups, but not the control group. SIV-Gag-specific CD8 T cells in the PB expressed alpha4beta7 integrin, the gut-homing receptor; a minor subset co-express alphaEbeta7 integrin. SIV-Gag-specific CD8 T cells were also detected in the gut tissue, intraepithelial (IEL) and lamina propria lymphocytes (LPL) of the duodenum and ileum. These cells were characterized by high levels of beta7 integrin expression and a predominance of the effector memory phenotype. Neither Il-12 nor IL-15 amplified the frequency of SIV-specific CD8 T cells in the gut. Thus, the DNA prime-oral Listeria boost strategy induced a mucosal SIV-Gag-specific CD8 T cell response characterized by expression of the alpha4beta7 integrin gut-homing receptor.

Two subspecies of rhesus (Rh) macaques, the Chinese (Ch) and Indian (Ind) subspecies were infected intravenously with 100TCID50 SIVmac239. CD4+, CD8+ T cells, plasma viral loads, depletion of intestinal lymphocytes with memory phenotype, humoral immune responses and clinical courses were monitored for 600 days. The pathogenesis of SIVmac was also compared with primary human immunodeficiency virus (HIV) infection of humans. Plasma viral loads in Ch Rh were lower in the acute and chronic phases compared with Ind Rh. SIVmac pathogenesis in Ch Rh was closer to virus loads in untreated HIV infected humans. Ch Rh had higher CD4/CD8 ratios, stronger antibody responses and interestingly, less depletion of intestinal memory CCR5+ CD4+ T lymphocytes compared with Ind Rh. One Ch Rh developed B cell origin lymphoma at 570 days post-infection, the first such report in this subspecies. Three of four Ind Rh developed AIDS within 6 months. The findings indicate that Ch Rh are more resistant to SIVmac pathogenesis compared with Ind Rh and that Ch Rh paralleled HIV-1 infections in untreated adult humans. The SIVmac infected Ch Rh subspecies are an acceptable model for HIV/AIDS.