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

HC Yang, S Xing, L Shan, K O'Connell… - The Journal of …, 2009 - Am Soc Clin Investig
HC Yang, S Xing, L Shan, K O'Connell, J Dinoso, A Shen, Y Zhou, CK Shrum, Y Han, JO Liu
The Journal of clinical investigation, 2009Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation