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. ! !
HIV, the virus that causes AIDS, is responsible for a pandemic that currently affects 36.7 million infected individuals, with an estimated 2.1 million new infections and 1.1 million deaths each year. While effective treatments for the symptoms of the infection exist, only 46% of infected individuals are receiving treatment and there is currently no cure (statistics from WHO as of December 2015). The aim of this proposal is to develop new approaches to allow an individual's immune system to recognize and eliminate HIV-infected cells as a strategy to cure what is currently a persistent, life-long infection. !
| Painter, Mark M; Zaikos, Thomas D; Collins, Kathleen L (2017) Quiescence Promotes Latent HIV Infection and Resistance to Reactivation from Latency with Histone Deacetylase Inhibitors. J Virol 91: |
