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.

Public Health Relevance

Antiretroviral therapy is able to suppress HIV replication without completely eliminating virus and the mechanism for HIV persistence is incompletely understood. Our studies test a new mechanism that Gag- mediated autophagy may promote the persistence of HIV reservoir. There is a reasonable expectation that approved autophagy-blocking drugs would reduce the half-life of latent infected cells, make them more susceptible to immune killing and help to eliminate the HIV latent reservoir.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI116256-01
Application #
8845322
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Stansell, Elizabeth H
Project Start
2015-06-23
Project End
2017-05-31
Budget Start
2015-06-23
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
$230,250
Indirect Cost
$80,250
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201