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Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation
Hung-Chih Yang, … , Joseph B. Margolick, Robert F. Siliciano
Hung-Chih Yang, … , Joseph B. Margolick, Robert F. Siliciano
Published October 1, 2009
Citation Information: J Clin Invest. 2009;119(11):3473-3486. https://doi.org/10.1172/JCI39199.
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Technical Advance AIDS/HIV

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

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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-κB 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.

Authors

Hung-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

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Figure 6

Screening of small-molecule libraries identifies 5HN as a candidate activator.

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Screening of small-molecule libraries identifies 5HN as a candidate acti...
(A) Summary of screening results from JHDL. The results were expressed as the percentage of GFP-positive cells after normalization to the response to anti-CD3 plus anti-CD28. For simplicity, only 500 drugs including the hits PMA and 5HN are shown. (B) Chemical structure of 5HN. (C) Effects of 5HN, PMA, and anti-CD3 plus anti-CD28 on the size of latently infected resting CD4+ T cells. Cell size was measured by flow cytometry using the forward scatter. (D) Effect of 5HN on the transcription of HIV-1. Latently infected Bcl-2–transduced cells were left unstimulated or were stimulated with the indicated concentrations of 5HN or anti-CD3 plus anti-CD28 antibodies. The levels of viral mRNA were quantified using real-time RT-PCR and were normalized to the β-actin mRNA levels. The fold change is shown relative to that observed in the unstimulated samples. Data are mean ± SD of triplicate samples from 1 of 2 independent experiments, all of which produced similar results.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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