Challenge Area: Translational Science Specific Challenge Topic 15-AI-101: Explore the earliest events in HIV infection and use this information to develop new interventions for preventing and treating HIV infection. Despite significant progress in HIV research, it is still unclear why the host immune response fails to control viral replication in most infected individuals. During the viral load ramp-up phase of acute HIV infection (AHI), there is an explosive production of pro-inflammatory and anti-viral cytokines. However, adaptive T cell responses only appear coincident with the fall in viral load. Studies of the events that transpire from initial infection to onset of plasma viremia are essential to understanding why effective immune responses are not induced soon after virus transmission and to identifying the barriers a vaccine must surmount. A critical event that defines AHI or SIV infection is massive virus-induced CD4+ T cell loss in the gut and in peripheral blood. The mechanisms underlying CD4+ T cell death include induction of cell death pathways by HIV proteins or direct infection of T cells with replicating virus. However, most dying CD4+ T cells are uninfected and so death results from indirect mechanisms such as the up-regulation of death pathway molecules such as TRAIL and its ligand DR5, as well as Fas ligand (FasL). Elevation of these factors has been described in both the eclipse and early viral ramp up phases. Concurrently, there is a substantial production of microparticles (MPs) which are released from apoptotic cells into the plasma. Recently we made the striking observation that apoptotic MPs or AHI plasma enriched in MPs directly suppress the activation of human dendritic cells (DCs) and the capacity of DCs to prime or boost antigen-specific T cells. Furthermore, DCs are induced to produce the immunosuppressive cytokine TGF? vs. pro-inflammatory cytokines. These effects, in addition to the capacity of MPs to suppress immunoglobulin production, suggest a means by which the adaptive immune response could be sharply curtailed during viral ramp up. The objectives of this proposal are to: (1) Determine how MPs modulate DC activation and subsequent innate and adaptive immune responses. Human DC subsets will be pre-exposed to MPs prepared from UV irradiated PBMC or HIV- infected T cells. Following stimulation with TLR agonists, DCs will be evaluated for expression of maturation markers, and production of pro-inflammatory or immunosuppressive cytokines. The subsequent T cell responses induced by MP-treated DCs will be evaluated for cytokines characteristic of Th1, Th2, Th17, or regulatory T cell responses. NK cell activation by MP-modulated DCs will also be examined. (2) Identify mechanisms of MP-mediated inhibition of DC function. The receptors on DCs which bind MPs will be identified and characterized. Receptors that confer immunosuppressive signals to DC will be determined using siRNA and/or blocking antibody approaches to reverse MP-mediated suppression. Signaling complexes associated with these receptors will be determined through immunopreciptation. (3) Identify the factor(s) in AHI plasma that suppress the adaptive immune response. AHI plasma enriched in MPs has similar effects to MPs prepared from irradiated PBMCs. AHI plasma is also enriched in several factors which may mediate similar effects e.g. soluble factors (TRAIL, FasL, TNFR2), virus and translocated LPS. Archived plasma from donors collected before, during and after the HIV-1 viral load ramp-up phase will be analyzed for their content and propensity to block DC activation and T cell priming. The specific factors that induce immuno-suppression will be identified. The identification of receptors and pathways that mediate this effect may lead to new prevention approaches and therapeutics.
Acute HIV infection, when diagnosed can be treated by institution of anti-viral therapies. Unfortunately, the therapy is unlikely to prevent the massive apoptosis that occurs concurrently or the ensuing immune suppression. By identifying mechanisms through which apoptotic particles or cells block the innate and adaptive immune responses, it may be possible to develop new therapeutic approaches to enhance immunity during these critical stages.
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