Mechanisms of HIV-1 persistence and strategies to elicit Cytotoxic T Lymphocyte-mediated clearance of infected cells

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Abstract Human Immunodeficiency Virus (HIV), which is responsible for a pandemic affecting 36.7 million infected individuals worldwide, establishes a persistent infection for which there is currently no cure. A primary mechanism by which the virus persists in an individual is the evasion of HIV- specific T cell responses, which are an essential component of antiviral adaptive immune responses. T cell responses require the presentation of viral peptides in the context of Major Histocompatibility Complex Class I (MHC-I) on the surface of infected cells, and HIV prevents this by two distinct mechanisms. First, the virus can establish a latent infection in which the viral genome has integrated into the host cell DNA but does not produce viral proteins, providing no HIV peptides for presentation to T cells. Subsequently, even when HIV proteins are being actively expressed, one of these viral proteins, Nef, hijacks intracellular trafficking pathways to divert MHC-I away from the cell surface, preventing T cell recognition. Thus, in order to elicit a successful T cell response as a cure strategy for HIV, both reversal of latency and inhibition of Nef will be required. I have developed and characterized a novel in vitro model of HIV latency in primary human hematopoietic stem and progenitor cells (HSPCs) in which quiescent HSPCs preferentially acquire a latent infection that is sustained in culture and resistant to reactivation approaches that are effective in proliferating cells. I will use this in vitro latency model to investigate the HSP-90-dependent gene networks responsible for regulating HIV latency in an unbiased fashion, and the role of HSP-90 in the regulation of T cell latency will be assessed. Additionally, previous work in our lab has identified a panel of inhibitors of Nef, purified from natural product extracts, which allow for expression of MHC-I on the cell surface in the presence of Nef. I will investigate the mechanism by which these inhibitors enhance MHC-I expression in the presence of Nef, and will then determine whether they are capable of promoting specific killing of HIV-infected cells by T cells. ! !