Depletion of latent HIV-1 infection in vivo: a proof-of-concept study.
BACKGROUND
Persistent infection in resting CD4+ T cells prevents eradication of HIV-1. Since the chromatin remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV, we tested the ability of the HDAC inhibitor valproic acid to deplete persistent, latent infection in resting CD4+ T cells.


METHODS
We did a proof-of-concept study in four volunteers infected with HIV and on highly-active antiretroviral therapy (HAART). After intensifying the effect of HAART with subcutaneous enfuvirtide 90 mug twice daily for 4-6 weeks to prevent the spread of HIV, we added oral valproic acid 500-750 mg twice daily to their treatment regimen for 3 months. We quantified latent infection of resting CD4+ T cells before and after augmented treatment by limiting-dilution culture of resting CD4+ T cells after ex-vivo activation.


RESULTS
The frequency of resting cell infection was stable before addition of enfuvirtide and valproic acid, but declined thereafter. This decline was significant in three of four patients (mean reduction 75%, range 68% to >84%). Patients had slight reactions to enfuvirtide at the injection site, but otherwise tolerated treatment well.


CONCLUSIONS
Combination therapy with an HDAC inhibitor and intensified HAART safely accelerates clearance of HIV from resting CD4+ T cells in vivo, suggesting a new and practical approach to eliminate HIV infection in this persistent reservoir. This finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future.
Lehrman
Ginger
G
University of Texas Southwestern Medical Center at Dallas, Department of Medicine, Division of Infectious Diseases, 5323 Harry Hines Boulevard, Dallas, TX 753901, USA.
Hogue
Ian B
IB
Palmer
Sarah
S
Jennings
Cheryl
C
Spina
Celsa A
CA
Wiegand
Ann
A
Landay
Alan L
AL
Coombs
Robert W
RW
Richman
Douglas D
DD
Mellors
John W
JW
Coffin
John M
JM
Bosch
Ronald J
RJ
Margolis
David M
DM
D019380:Anti-HIV Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D014635:Valproic Acid / Q000494:pharmacology*
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; D000077560:Enfuvirtide; D014635:Valproic Acid