Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression.
BACKGROUND
Histone deacetylase (HDAC), a host mediator of gene repression, inhibits HIV gene expression and virus production and may contribute to quiescence of HIV within resting CD4 T cells.


OBJECTIVE
To test the ability of valproic acid (VPA), an inhibitor of HDAC in clinical use, to induce expression of HIV from resting CD4 T cells.


METHODS
Chromatin immunoprecipitation measured the capability of VPA to deacetylate the HIV promoter, a remodeling of chromatin linked to gene expression. The effect of VPA on resting CD4 T cell phenotype was measured by flow cytometric analysis, and its effect on de novo HIV infection of peripheral blood mononuclear cells was measured ex vivo. Outgrowth of HIV from resting CD4 T cells of aviremic, HIV-infected donors treated with highly active antiretroviral therapy was compared in limiting-dilution cultures after mitogen stimulation or exposure to VPA.


RESULTS
VPA induced acetylation at the integrated HIV proviral promoter, but CD4 cells exposed to VPA did not become activated or more permissive for de novo HIV infection. VPA induced outgrowth of HIV from the resting CD4 cells of aviremic patients at concentrations achievable in vivo as frequently as did mitogen stimulation.


CONCLUSIONS
With advances in antiretroviral therapy, HIV infection might be cleared by intensive time-limited treatment coupled with practical strategies that disrupt latency without enhancing new infection. HDAC inhibitors are capable of inducing expression of quiescent provirus, without fully activating cells or enhancing de novo infection, and may be useful in future clinical protocols that seek to eradicate HIV infection.
Ylisastigui
Loyda
L
Department of Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Archin
Nancie M
NM
Lehrman
Ginger
G
Bosch
Ronald J
RJ
Margolis
David M
DM
D000107:Acetylation; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D004197:Disease Reservoirs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000302:isolation & purification*; D056572:Histone Deacetylase Inhibitors; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid