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Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation.

Abstract
The development of highly active antiretroviral therapy (HAART) to treat individuals infected with HIV-1 has dramatically improved patient outcomes, but HAART still fails to cure the infection. The latent viral reservoir in resting CD4+ T cells is a major barrier to virus eradication. Elimination of this reservoir requires reactivation of the latent virus. However, strategies for reactivating HIV-1 through nonspecific T cell activation have clinically unacceptable toxicities. We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4+ T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4+ T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthalene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-kappaB without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge latent virus. Our study expands the number of classes of latency-reversing therapeutics and demonstrates the utility of this in vitro model for finding strategies to eradicate HIV-1 infection.
AuthorsHung-Chih Yang, Sifei Xing, Liang Shan, Karen O'Connell, Jason Dinoso, Anding Shen, Yan Zhou, Cynthia K Shrum, Yefei Han, Jun O Liu, Hao Zhang, Joseph B Margolick, Robert F Siliciano
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 119 Issue 11 Pg. 3473-86 (Nov 2009) ISSN: 1558-8238 [Electronic] United States
PMID19805909 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Small Molecule Libraries
Topics
  • CD4-Positive T-Lymphocytes (virology)
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • HIV-1 (drug effects, physiology)
  • Humans
  • Lymphocyte Activation (drug effects)
  • Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
  • Reactive Oxygen Species
  • Signal Transduction
  • Small Molecule Libraries (chemistry, pharmacology)
  • Transduction, Genetic
  • Virus Activation (drug effects)
  • Virus Latency (drug effects)

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