Defining the mechanisms of action of drug candidates that can reactivate latent proviruses presents formidable challenges both because studies ofthe physiological mechanisms responsible for proviral reactivation are incomplete and because there are no universally accepted primary cell models for HIV and SIV latency that can be used to support the development of new drugs. This project has been designed to address these critical Collaboratory strategic needs by defining how the sequential activation of multiple signaling pathways modifies the duration and magnitude ofthe HIV transcriptional response in primary cell models for HIV latency and by defining the role of the accessory protein Nef in establishing and maintaining HIV and SIV latency. We hypothesize that sustained HIV proviral reactivation minimally requires both the activation of P-TEFb and the sequential activation of NF-Kappa B, NFAT and AP-1. As part of our further development ofthe primary cell model we have recently made the surprising and discovery that proviral silencing is strongly enhanced in cells infected with viruses expressing Nef. We hypothesize that disruption of cell signaling pathways by Nef creates an environment that promotes viral entry into latency. Since Nef has long been known to enhance viral replication and spread, the obsen/ation that Nef also increases the frequency of HIV silencing raises the intriguing possibility that proviral latency is an important mechanism used to disseminate viruses eariy during infections and to escape the strong immune responses mounted during acute infections. In the course of these studies we will be interacting closely with other Collaboratory investigators. Key interactions will include the detailed evaluation of candidate drugs in our pipeline (Hazuda), development of latency models in primary cells (Planelles), development of latency models for SIV (Clements), and evaluation of new cellijlar factors that contribute to the maintenance of HIV latency (Greene, Verdin, Ofi and Peteriin).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096113-03
Application #
8497425
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$312,503
Indirect Cost
$23,256
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Davis, Zachary B; Cogswell, Andrew; Scott, Hamish et al. (2016) A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells. PLoS Pathog 12:e1005421
Imaz, Arkaitz; Martinez-Picado, Javier; Niubó, Jordi et al. (2016) HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen. J Infect Dis 214:1512-1519
Honeycutt, Jenna B; Wahl, Angela; Baker, Caroline et al. (2016) Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest 126:1353-66
Tokarev, Andrey; Stoneham, Charlotte; Lewinski, Mary K et al. (2016) Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1. J Virol 90:2486-502
Victor Garcia, J (2016) Humanized mice for HIV and AIDS research. Curr Opin Virol 19:56-64
Smith, Davey M; Nakazawa, Masato; Freeman, Michael L et al. (2016) Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment. Clin Infect Dis 63:1517-1524
Gianella, Sara; Anderson, Christy M; Var, Susanna R et al. (2016) Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection. J Virol 90:3944-52
Garcia, J Victor (2016) In vivo platforms for analysis of HIV persistence and eradication. J Clin Invest 126:424-31
Lee, Sook-Kyung; Zhou, Shuntai; Baldoni, Pedro L et al. (2016) Quantification of the Latent HIV-1 Reservoir Using Ultra Deep Sequencing and Primer ID In A Viral Outgrowth Assay. J Acquir Immune Defic Syndr :
Wagner, Gabriel A; Chaillon, Antoine; Liu, Siqi et al. (2016) HIV-associated neurocognitive disorder is associated with HIV-1 dual infection. AIDS 30:2591-2597

Showing the most recent 10 out of 187 publications