The latent reservoir for HIV-1 in resting CD4+ T cells is a major barrier to virus eradication. There is great current interest in potential strategies for eliminating this reservoir. During the previous funding period, we have carried out mechanistic studies that have led to a reevaluation of current models of latency and have shown that mechanisms of latency are most accurately analyzed in primary cell systems rather than in transformed T cell lines. We developed an in vitro system in which primary resting CD4+ T cells carrying latent HIV-1 genomes can be generated. In this proposal, we describe the use of this system to identify and characterize small molecules capable of reactivating latent HIV-1 for use in efforts to eradicate this reservoir. We have already identified one promising hit which we will characterize mechanistically. In addition, we will use this system to explore key unanswered questions regarding the dynamics of the latent reservoir, focusing on issues that are important for eradication strategies.
The Specific Aims are (1) to determine the mechanism by which the identified hit (5-hydroxy-1,4-naphthoquinone) reactivates latent HIV-1, (2) to use the novel latency model in primary resting CD4+ T cells to screen selected small molecule libraries for other agents that reactivate latent HIV-1 without inducing global T cell activation, (3) to carry out a comparative in vitro evaluation of the efficacy of agents that reactivate latent HIV-1, and (4) to use the primary cell model to explore mechanisms involved in the maintenance of HIV-1 latency.
HIV can persist in a silent or latent form even in patients who are treated with potent antiviral drugs. Curing HIV infection will require new ways to eliminate this latent reservoir. The studies proposed here are designed to find new drugs that can eliminate this latent reservoir.
|Bruner, Katherine M; Murray, Alexandra J; Pollack, Ross A et al. (2016) Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med 22:1043-9|
|Deng, Kai; Pertea, Mihaela; Rongvaux, Anthony et al. (2015) Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517:381-5|
|Norton, T D; Miller, E A; Bhardwaj, N et al. (2015) Vpx-containing dendritic cell vaccine induces CTLs and reactivates latent HIV-1 in vitro. Gene Ther 22:227-36|
|Bruner, Katherine M; Hosmane, Nina N; Siliciano, Robert F (2015) Towards an HIV-1 cure: measuring the latent reservoir. Trends Microbiol 23:192-203|
|Blankson, Joel N; Siliciano, Janet D; Siliciano, Robert F (2014) Finding a cure for human immunodeficiency virus-1 infection. Infect Dis Clin North Am 28:633-50|
|Kim, Michelle; Hosmane, Nina N; Bullen, C Korin et al. (2014) A primary CD4(+) T cell model of HIV-1 latency established after activation through the T cell receptor and subsequent return to quiescence. Nat Protoc 9:2755-70|
|Shan, Liang; Xing, Sifei; Yang, Hung-Chih et al. (2014) Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ T cells. J Antimicrob Chemother 69:28-33|
|Bullen, C Korin; Laird, Gregory M; Durand, Christine M et al. (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20:425-9|
|Siliciano, Janet D; Siliciano, Robert F (2014) Recent developments in the search for a cure for HIV-1 infection: targeting the latent reservoir for HIV-1. J Allergy Clin Immunol 134:12-9|
|Durand, Christine M; Ambinder, Richard F (2013) Hematopoietic stem cell transplantation in HIV-1-infected individuals: clinical challenges and the potential for viral eradication. Curr Opin Oncol 25:180-6|
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