This Collaboratory application focuses on the best understood reservoir for HIV-1, the latent reservoir in resting CD4+ T cells. Our goal is to find small molecule approaches for targeting this reservoir. However, HlV-1 may also persist in other reservoirs in patients on H/ ART. Therefore a comprehensive approach to HIV-1 eradication requires the identification of all stable reservoirs and the development of strategies to eliminate each one. To this end, our laboratory has been analyzing the trace levels of residual viremia (RV) that can be detected using specialized assays in patients on HAART who have """"""""undetectable"""""""" viral loads by standard clinical assays. Because of the short half-life of free virus in the plasma, the presence of RV in patients on long term HAART indicates the ongoing production of virus in the presence of effective drugs. Thus, the analysis of RV provides a unique window into the state of virologic suppression and the reservoirs that stand in the way of eradication. Through sequence analysis of the trace levels of RV present in patients on HAART, our group and others have provided evidence that at least some fraction of the RV is derived from a source distinct from the latent reservoir in resting CD4+ T cells. The goals of the this project are to carry out exhaustive longitudinal sampling of the RV and the latent reservoir in unique patient populations and to compare the sequences from these two sources in order to verify the existence of additional reservoirs. Parallel studies will be carried out in SIV-infected macaques on HAART in a effort to find the source of the RV. Definitave demonstration of the existence of additional reservoirs contributing to RV will may require the development of alternative therapeutic approaches in addition to those targeting the latent reservoir in resting CD4+ T cells. Assessing the response of alternative reservoirs to strategies targeting the latent reservoir in initial clinical trials may provide critical information about the need for additional approaches to achieve eradication.

Public Health Relevance

Curing HIV infection requires finding all of the reservoirs in the body where the virus can persist in patients on antiretroviral therapy. One reservoir has been identified, but there may be more. This application seeks to determine whether additional reservoirs exist. If so, novel strategies must be designed to eliminate them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096113-02
Application #
8377521
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$1,210,550
Indirect Cost
$32,694
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Beliakova-Bethell, Nadejda; Hezareh, Marjan; Wong, Joseph K et al. (2017) Relative efficacy of T cell stimuli as inducers of productive HIV-1 replication in latently infected CD4 lymphocytes from patients on suppressive cART. Virology 508:127-133
Martin, Alyssa R; Pollack, Ross A; Capoferri, Adam et al. (2017) Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity. J Clin Invest 127:651-656
Yek, Christina; Massanella, Marta; Peling, Tashi et al. (2017) Evaluation of the Aptima HIV-1 Quant Dx Assay for HIV-1 RNA Quantitation in Different Biological Specimen Types. J Clin Microbiol 55:2544-2553
Lee, Sook-Kyung; Zhou, Shuntai; Baldoni, Pedro L et al. (2017) Quantification of the Latent HIV-1 Reservoir Using Ultra Deep Sequencing and Primer ID in a Viral Outgrowth Assay. J Acquir Immune Defic Syndr 74:221-228
Boehm, Daniela; Ott, Melanie (2017) Flow Cytometric Analysis of HIV-1 Transcriptional Activity in Response to shRNA Knockdown in A2 and A72 J-Lat Cell Lines. Bio Protoc 7:
Chaillon, Antoine; Nakazawa, Masato; Wertheim, Joel O et al. (2017) No Substantial Evidence for Sexual Transmission of Minority HIV Drug Resistance Mutations in Men Who Have Sex with Men. J Virol 91:
Sung, Julia A; Sholtis, Katherine; Kirchherr, Jennifer et al. (2017) Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells. EBioMedicine 23:52-58
Akrami, Kevan; Coletta, Joelle; Mehta, Sanjay et al. (2017) Gordonia sternal wound infection treated with ceftaroline: case report and literature review. JMM Case Rep 4:e005113
Gianella, Sara; Taylor, Jeff; Brown, Timothy R et al. (2017) Can research at the end of life be a useful tool to advance HIV cure? AIDS 31:1-4
Bosque, Alberto; Nilson, Kyle A; Macedo, Amanda B et al. (2017) Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation. Cell Rep 18:1324-1334

Showing the most recent 10 out of 209 publications