Although combination antiretroviral therapy (cART) can reduce plasma HIV RNA levels in most infected individuals to below the detection limit of clinical assays, it is not curative and persistent viremia is detected in the majority of patients.A rare, but extremely stable, HIV proviral DNA reservoir in resting CD4+ T cells (i.e. the latent reservoir) is thought to be the major source of persistent viremia. This latent reservoir can produce infectious virus when the host cell is reactivated by recall antigen (or by various cytokines), that can reseed HIV infection if cART is discontinued. Eradication of the latent reservoir may lead to a cure for HIV infection. Currently, a kick and kill strategy is being testd in ongoing clinical trials as a pharmacological approach to deplete the latent HIV reservoir. This strategy involves the administration of a latency reversing agent (LRA) which induces HIV out of latency (the kick), that in turn facilitates death of the infected cells by viral cytopathic effets (the kill). Several distinct therapeutic classes of LRAs have been identified that effectively kick HIV out of latency. In contrast, our understanding of the kill in HIV-infected resting CD4 T cells is extremely limited. The primary goal of this study is to comprehensively assess the kill in the kick and kill strategy, using novel primary cell models of latency in highly purified nae (TN) and central memory (TCM) CD4+ T cells. Collectively, we anticipate that these studies will yield important insights into HIV persistence, and may have the potential to identify new targets or approaches to eradicate latent HIV infection. Furthermore, they could help explain clinical finding from ongoing trials that are focused on depleting the latent HIV reservoir.
A 'kick and kill' strategy is being tested in ongoing clinical trials as a pharmacological approach to deplete the latent HIV reservoir. The primary goal of this study is to comprehensively assess the 'kill' in the 'kick and kill' strategy, using novel primary cell models of latency in highly purified nave (TN) and central memory (TCM) CD4+ T cells. Collectively, we anticipate that these studies will yield important insights into HIV persistence, and may have the potential to identify new targets or approaches to eradicate latent HIV infection.
| Sanyal, Anwesha; Mailliard, Robbie B; Rinaldo, Charles R et al. (2017) Novel assay reveals a large, inducible, replication-competent HIV-1 reservoir in resting CD4+ T cells. Nat Med 23:885-889 |
| Zerbato, Jennifer M; Tachedjian, Gilda; Sluis-Cremer, Nicolas (2017) Nonnucleoside Reverse Transcriptase Inhibitors Reduce HIV-1 Production from Latently Infected Resting CD4+ T Cells following Latency Reversal. Antimicrob Agents Chemother 61: |
| Gupta, Phalguni; Sanyal, Anwesha; Mailliard, Robbie B (2017) TZA: a novel assay for measuring the latent HIV-1 reservoir. Expert Rev Mol Diagn 17:1033-1035 |
| Zerbato, Jennifer M; Serrao, Erik; Lenzi, Gina et al. (2016) Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4+ T Cells In Vitro. J Virol 90:8059-73 |
