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. 2005 Aug;366(9485):549-55.
doi: 10.1016/S0140-6736(05)67098-5.

Depletion of latent HIV-1 infection in vivo: a proof-of-concept study

Ginger Lehrman  1 , Ian B Hogue, Sarah Palmer, Cheryl Jennings, Celsa A Spina, Ann Wiegand, Alan L Landay, Robert W Coombs, Douglas D Richman, John W Mellors, John M Coffin, Ronald J Bosch, David M Margolis
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Depletion of latent HIV-1 infection in vivo: a proof-of-concept study

Ginger Lehrman et al. Lancet. 2005 Aug.

Abstract

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.

Procedures: 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.

Findings: 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.

Interpretation: 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.

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Figure 1
Figure 1
Effect of T-20 and VPA on resting CD4 cell IUPB: Pooled estimates of the number of cells (◆) containing replication-competent HIV per billion resting CD4+ cells (IUPB) on prolonged HAART, and after 16-18 weeks of continued HAART with VPA and T-20 as assayed by limiting-dilution culture is shown. Also displayed is the predicted decay of IUPB (half-life of 44.2 months; Siliciano 2003), and accelerated decay (half-life of 10.3 months; Ramratnam 2004) reported following intensified antiretroviral therapy. For illustrative purposes only, an estimate of half-life following T-20 and VPA therapy is displayed.
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