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

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.

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.