Persistent HIV infection of memory CD4+ T cells is a critical obstacle to eradication of HIV-1 infection. Agents must be developed that expose this viral reservoir to therapeutic intervention, without augmenting de novo HIV infection. The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has recently been shown to induce resting CD4 depletion in the context of intensified antiretroviral therapy (ART). In ex vivo studies of HIV+ patients'primary cells, we have tested several novel HDACi as well as hexamethylene-bisacetamide (HMBA), a novel inducer of P-TEFb activity, critical to the induction of quiescent HIV. However testing of these novel candidates, especially in combinatorial approaches, cannot be practically performed in ex vivo assays of human cells, or safely and rapidly tested in pilot clinical trials. We, therefore, will establish fully suppressive ART in a novel murine model carrying a reconstituted human immune system supportive of viral pathogenesis. Once ART in this system is validated, we will test the ability of HDACi and other reagents to delay or prevent recurrence of viremia after ART interruption. We will also attempt to quantitate infection of resting CD4+ T cells and document specific depletion of this cell population mediated by agents that disrupt latent infection.
Persistent, quiescent infection of resting CD4+ T cells is established early in infection and maintained despite antiretroviral therapy (ART). Given the challenges of lifelong suppressive HIV therapy, therapies that allow the clearance of the latent reservoir may allow eradication of HIV infection in future. We will establish suppressive ART in a novel murine model and validate persistent infection of human CD4+ T cells despite ART, thus providing a model system to study HIV-1 latency and test approaches to deplete persistent HIV infection.
| Denton, P W; Nochi, T; Lim, A et al. (2012) IL-2 receptor ?-chain molecule is critical for intestinal T-cell reconstitution in humanized mice. Mucosal Immunol 5:555-66 |
| Choudhary, Shailesh K; Archin, Nancie M; Cheema, Manzoor et al. (2012) Latent HIV-1 infection of resting CD4? T cells in the humanized Rag2?/? ?c?/? mouse. J Virol 86:114-20 |
| Denton, Paul W; Olesen, Rikke; Choudhary, Shailesh K et al. (2012) Generation of HIV latency in humanized BLT mice. J Virol 86:630-4 |
| Choudhary, Shailesh K; Margolis, David M (2011) Curing HIV: Pharmacologic approaches to target HIV-1 latency. Annu Rev Pharmacol Toxicol 51:397-418 |
| Choudhary, Shailesh K; Rezk, Naser L; Ince, William L et al. (2009) Suppression of human immunodeficiency virus type 1 (HIV-1) viremia with reverse transcriptase and integrase inhibitors, CD4+ T-cell recovery, and viral rebound upon interruption of therapy in a new model for HIV treatment in the humanized Rag2-/-{gamma}c- J Virol 83:8254-8 |
