Combinatorial latency reactivation for HIV-1 subtypes and variants.
The eradication of HIV-1 will likely require novel clinical approaches to purge the reservoir of latently infected cells from a patient. We hypothesize that this therapy should target a wide range of latent integration sites, act effectively against viral variants that have acquired mutations in their promoter regions, and function across multiple HIV-1 subtypes. By using primary CD4(+) and Jurkat cell-based in vitro HIV-1 latency models, we observe that single-agent latency reactivation therapy is ineffective against most HIV-1 subtypes. However, we demonstrate that the combination of two clinically promising drugs-namely, prostratin and suberoylanilide hydroxamic acid (SAHA)-overcomes the limitations of single-agent approaches and can act synergistically for many HIV-1 subtypes, including A, B, C, D, and F. Finally, by identifying the proviral integration position of latent Jurkat cell clones, we demonstrate that this drug combination does not significantly enhance the expression of endogenous genes nearest to the proviral integration site, indicating that its effects may be selective.
Burnett
John C
JC
Department of Chemical Engineering and Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA.
Lim
Kwang-Il
KI
Calafi
Arash
A
Rossi
John J
JJ
Schaffer
David V
DV
Arkin
Adam P
AP
D019380:Anti-HIV Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D009154:Mutation; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects
D019380:Anti-HIV Agents