GB virus C (GBV-C) is an enigmatic RNA virus. HIV+ people infected with GBV-C exhibit delayed progression to AIDS, a phenomenon we term GBV-C mediated protection from AIDS (GPFA). Though this protective effect has been substantiated by multiple studies, the mechanism of protection is unknown. There are at least three reasons why GPFA is understudied: (1) GBV-C grows poorly in vitro, (2) there is no animal model for exploring GPFA, and (3) human studies have focused almost entirely on cross-sectional sampling of blood, while we have now demonstrated that GBV-C RNA is much more abundant in other tissues, specifically the spleen and bone marrow. We developed an animal model to study GPFA by infecting macaques with GBV-C isolated from wild baboons. Importantly, we have shown that GBV-C infects both SIV+ and SIV-naive macaques and that macaque GBV-C infection recapitulates key features of human GBV-C infection: it causes high-titer, persistent viremia without any overt signs of disease. We have already used this model to demonstrate that GBV-C RNA is ~1,000x more abundant in spleen and bone marrow than blood. We hypothesize that GBV-C mediates protection from AIDS by directly interfering with lymphocyte activation, particularly in those tissues where GBV-C RNA is concentrated. To test this hypothesis, we will study GPFA in our pioneering model for GBV-C/SIV co-infection. Specifically, we will:
Specific Aim 1 : Determine the impact of GBV-C infection on peripheral immunity in the presence and absence of SIV co-infection. We will measure peripheral immune activation, virus-specific adaptive immunity, SIV-mediated immune pathology, and the effect of GBV-C on SIV pathogenesis during both acute and chronic infections. These experiments are essential for reconciling previous, conflicting observations about GPFA from studies of human blood.
Specific Aim 2 : Evaluate GBV-C-mediated immune activation in bone marrow, spleen, and gut mucosal tissues. We will compare immune activation between the bone marrow and blood from GBV-CSIV-experimentally-infected macaques and GBV-CHIV human volunteers. We will also characterize immune activation in the spleen and gut mucosa, two tissues where GBV-C and HIV/SIV, respectively, are concentrated. Understanding GPFA could have important practical implications. Aberrant immune activation is observed even in HIV+ patients treated with antiretrovirals; GBV-C might have therapeutic value if it interferes with immune activation. Furthermore, an estimated 7 million people eligible for ARV treatment remain untreated. GBV-C (or treatments that mimic its effects) could be a safe and simple healthspan extending treatment in settings where ARV access is low. This project is led by investigators experienced in HIV/SIV pathogenesis, novel virus characterization, and GBV-C immunology and pathogenesis. We are uniquely qualified to undertake this ambitious project.
People co-infected with HIV and GB virus C (GBV-C) have lower mortality and slowed progression to AIDS. We will study GBV-C/SIV co-infected monkeys and GBV-C/HIV co-infected people to test the hypothesis that GBV-C's protective effect is mediated by reduced immune activation, particularly in tissues that support high-levels of GBV-C and/or HIV/SIV replication.
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