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

نویسندگان

  • 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
چکیده

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.

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عنوان ژورنال:
  • The Journal of clinical investigation

دوره 119 11  شماره 

صفحات  -

تاریخ انتشار 2009