The role of microRNAs in premature T cell aging during HIV infection The overall goal of this proposal is to elucidate the mechanisms by which HIV infection induces premature T cell aging through regulation of microRNAs (miRNAs) and leading to blunted immune responses, with an aim to develop effective strategies to interfere with host mechanisms that contribute to viral persistence. This proposal is based on the fact that, while optimized antiretroviral therapy (ART) has resulted in long-term suppression of HIV replication, the interplay between HIV-associated immune dysregulation and HIV persistence during ART remains complex and incompletely understood. Several immunological abnormalities persist, including incomplete recovery of T cell functions and a lower rate of vaccine response. Thus, studies are needed to determine mechanisms of host machinery involvement in HIV persistence. The development of immune-based strategies that control viral replication would be very relevant for defining the path to a functional cure. Such strategies might be also limit the replenishment of viral reservoirs that may occur through ongoing replication in treated subjects and hence could help to achieve a sterilizing cure. It is not feasible for the tens of millions of people living with HIV infection to access and adhere to a lifetime of ART. Therefore, identifying a strategy to enhance immune-mediated clearance of virus-producing cells is of high priority. Our recent data suggest that individuals well-controlled on ART (with reasonable CD4 counts, low or undetectable viral loads) exhibit persistent elevation of markers of immune exhaustion and T cell aging, including PD-1/Tim-3 and KLRG1/DUSP6 regulatory proteins, which is associated with disruption of miR-181a expression in functionally impaired CD4 T cells. Since miRNAs have been implicated in the regulation of both virus replication and cell function, we hypothesize that an HIV-mediated decline of miR-181a may induce premature T cell aging by up-regulating KLRG1/DUSP6 or PD-1/Tim-3; thus, reconstituting miR-181a or manipulating its targeted proteins may rescue impaired CD4 T cell functions and subsequently enhance the host capacity to control persistent viral infection. To test this hypothesis, we will carry out the following two specific aims:
Aim 1 will define the transcriptional and translational mechanisms that control miR-181a expression in CD4 T cells of HIV-infected individuals on ART;
Aim 2 will determine the role of miR-181a in regulating KLRG1/DUSP6 expression in CD4 T cells of HIV-infected individuals on ART. This translational study is significant in that it explores mechanisms by which HIV-induced, miRNA- mediated T cell aging results in HIV persistence during ART.
Cure of HIV infection has become a major goal for the 21st century. While multiple mechanisms are likely to contribute to HIV persistence, the interplay between HIV-associated immune responses and HIV persistence during effective antiretroviral therapy (ART) remains complex and incompletely understood. This R15 project will study immune-based strategies to enhance immune-mediated clearance of HIV-producing cells by testing the role of miR- 181a in regulating CD4+ T cell function during ART, and evaluating the expression and immune function of negative regulators (PD-1, TIM-3, KLRG1, DUSP6) in CD4+ T cells from individuals on ART. It will provide key information for better defining the role of miRNAs and other immune mechanisms in controlling HIV. Therefore, this study is fundamentally important, clinically significant, timely, and highly relevant to public health.
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