Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation.
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.
Yang
Hung-Chih
HC
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Xing
Sifei
S
Shan
Liang
L
O'Connell
Karen
K
Dinoso
Jason
J
Shen
Anding
A
Zhou
Yan
Y
Shrum
Cynthia K
CK
Han
Yefei
Y
Liu
Jun O
JO
Zhang
Hao
H
Margolick
Joseph B
JB
Siliciano
Robert F
RF
D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014161:Transduction, Genetic; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries