Research Project
9193336
? DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infection creates a persistent reservoir in resting CD4 T cells that is maintained during antiretroviral therapy (ART). These reservoir CD4 T cells threaten recrudescence even after prolonged treatment and are a major impediment to AIDS cure. Our goals are to discover the mechanisms responsible for persistence of latent CD4 T cells and develop strategies to allow their elimination during a relevant time interval. We hypothesize that HIV developed a capacity to stimulate anti-apoptotic activities as a key part of the latency mechanism, which might account for the greatly increased half-life of reservoir cells and their evasion of immune clearance. Some studies indicated that low-level viral gene expression exists in some of the latently infected cells, even f they are not releasing infectious virus. Particularly, directly infected resting CD4 T cells produc Gag without spreading infection in a model of HIV latency. In this project, we focus on HIV Gag polyprotein, which induces autophagy in CD4 T cells and protect cells from apoptosis. Using some in vitro models of latency, we test whether Gag induced autophagy protect HIV latently infected cells from stress- induced apoptosis and CTL-mediated immune clearance, and whether specific autophagy inhibitors eliminate the resistance and help clear the latent cells. We will also map the active regions within Gag polyprotein and define the cytoprotective mechanisms of Gag-mediated autophagy. Specifically, we test whether Gag- mediated autophagy protect cells by selectively degrading pro-apoptotic proteins, damaged mitochondria and CTL-derived granzyme B. Chloroquine and its analog hydroxychloroquine are used widely as anti-malarial or anti-rheumatoid agents and are now used for cancer therapy as autophagy inhibitors. It is reasonable that our in vitro studies can provide the justification for animal modls or clinical trials testing whether autophagy inhibitors help eradicate HIV latent reservoir.
