| 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. |
| 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
(Affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.)
|
| Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 119
Issue 11
Pg. 3473-86
(Nov 2009)
ISSN: 1558-8238 [Electronic] United States |
| PMID | 19805909
(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)
|
