Latently infected, quiescent CD4 T cells represent a central obstacle to eradication of HIV-1. Major hurdles are the low frequencies of latently infected cells in peripheral blood and the lack of known phenotypic markers that can distinguish them from uninfected ones. These impediments have prompted the development of in vitro cell models of latency. Such models allow manipulation of cellular and viral characteristics to gain a mechanistic understanding of how latency is established and regulated. However, no single experimental system of HIV latency is perceived to completely recapitulate the biology of the latent viral reservoir in vivo. This is mainly because (a) the mechanisms for establishment of latency by HIV are multiple;and (b) the types of cells harboring latent infection are also multiple. A wealth of knowledge has been gained regarding how specific stimuli (e.g. activation/differentiation, homeostatic proliferation, cytokines) and viral factors (e.g. integration site, Tat-driven expression) influence the dynamics of latent reservoirs in experimental systems. Project 2.2 will perform

Public Health Relevance

Within the Delaney Collaboratory program, the overall goal of Project 2.2 is the application of in vitro primary cell culture systems to identify new small molecule drugs and drug combinations that will activate latent HIV in biological systems, prior to studies conducted in animals and humans. A second aspect of these studies is to initiate identification of the mechanisms of action of such drugs to enable further studies that can focus on the identification of novel cellular targets and pathways, which will broaden of the scope of available therapeutic possibilities in the near future.

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 #
8497432
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
$283,008
Indirect Cost
$23,255
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Honeycutt, Jenna B; Liao, Baolin; Nixon, Christopher C et al. (2018) T cells establish and maintain CNS viral infection in HIV-infected humanized mice. J Clin Invest 128:2862-2876
Power, Jennifer; Westle, Andrew; Dowsett, Gary W et al. (2018) Perceptions of HIV cure research among people living with HIV in Australia. PLoS One 13:e0202647
Marsden, Matthew D; Wu, Xiaomeng; Navab, Sara M et al. (2018) Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology 520:83-93
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

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