No one with HIV infection has been cured, despite the development of effective antiretroviral therapy. Nevertheless, stable remission or cure of infection is the ultimate goal of HIV therapy. The difficulties of lifelong therapy make it imperative to understand the obstacles to eradication of HIV infection. Several molecular mechanisms restrict proviral expression and can contribute to proviral persistence. Targeted therapeutics directed at these mechanisms may therefore be developed, designed to augment HIV promoter and viral expression without global T cell activation or increased de novo HIV infection. Such agents that induce expression of latent HIV but do not enhance de novo infection would be a major advance towards the eradication of HIV infection. Three collaborative projects will allow iterative evaluation and development of reagents to interrupt HIV latency. Project 1 will identify novel drug candidates to target persistent HIV infection, evaluate the effects of these agents on human gene expression, and perform preclinical assessment of PK/PD in pilot studies. Project 2 will establish the fully suppressive antiviral therapies in the BLT murine model of HIV infection, and test the ability of reagents to delay or prevent viral rebound after the interruption of antiviral therapy. Project 3 will establish tissue culture testing platforms, perform ex vivo studies in resting CD4 T cells obtained from HIV-infected volunteers, and implement a human study to deplete HIV infection in resting T cells. This IPCP collaborative will evaluate new anti-latency therapeutics in a continuum of cell culture models, a novel murine model, and primary human cells, leading ultimately to the rational implementation of human trials to target HIV latency and move towards eradication of HIV infection.
Anti-retroviral therapy has not lead to the eradication of virus from HIV-infected individuals. This is due in part to the ability of HIV to establish latency in resting CD4+ T-lymphocytes. Our approach to overcome HIV latency is to develop agents capable of inducing expression of quiescent HIV without enhancing new infection, so that persistent viral infection may be cleared. We will study novel candidate anti-latency drugs in a novel mouse model system, in cells from HIV infected patients, and ultimately in patients. PROJECT 1: [TITLE (Hazuda, D)] PROJECT 1 DESCRIPTION (provided by applicant): The long term goal of therapy for HIV-1 infection should be to develop treament regimens which can provide durable control of viral replication and/or eradicate the infection. Included among the limitations of current therapy is the incomplete suppression of viral replication in many patients and the inability to targent persistent, replication-competent proviral genomes. While new agents in development may enhance the overall potency and long term durability of antretroviral treatments, these will not address the long term problem of latency. The current program application proposes to evalaute the hypothesis that therapeutics can be developed that can disrupt proviral quiescence in vivo. This hypothesis is based on in vitro observations that have provided compelling evidence that HIV-1 latency is maintained by cellular mechanisms which affect chromatin and regulate cofactor availability to the provirus. These studies demonstrate that derepression of HIV-1 transcription can be induced without activating T-cells. In Project 1 of this Program, we will identify novel molecules that induce the expression of latent provirus, and provide these reagents for studies in the BLT mouse model (Project 2), and in primary human cell systems and clinical experiments (Project 3). The objectives of Project 1 include providing potent integrase inhibitors for a novel combination regimen (ART) that will be effective in fully suppressing HIV replication in the BLT mouse model, to identify novel inducers of latent proviral expression, and to use biomarker assays to prioritize these molecules for further study in Projects 2 and 3. The overall objective is to identify mechanisms for therapeutic targeting to disrupt HIV latency, and assess the susceptibility of proviral genomes to therapeutic intervention, with the ultimate goal of establishing treatment paradigms suitable for clinical testing.
Despite antiviral therapy, eradication of HIV infection is unachievable as the virus can establish latency in CD4+ cells. This Project will seek to develop agents capable of inducing expression of quiescent HIV without enhancing new infection, so that persistent viral infection may be cleared. Within the Integrated Program, we will facilitate the study of """"""""anti-latency therapy"""""""" on cells from HIV infected patients, and in model systems to move towards reagents might be used in future efforts to clear HIV infection.
| Manson McManamy, Mary E; Hakre, Shweta; Verdin, Eric M et al. (2014) Therapy for latent HIV-1 infection: the role of histone deacetylase inhibitors. Antivir Chem Chemother 23:145-9 |
| Margolis, David M; Hazuda, Daria J (2013) Combined approaches for HIV cure. Curr Opin HIV AIDS 8:230-5 |
| Denton, Paul W; Olesen, Rikke; Choudhary, Shailesh K et al. (2012) Generation of HIV latency in humanized BLT mice. J Virol 86:630-4 |
| 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 |
| Friedman, Julia; Cho, Won-Kyung; Chu, Chung K et al. (2011) Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J Virol 85:9078-89 |
| Choudhary, Shailesh K; Margolis, David M (2011) Curing HIV: Pharmacologic approaches to target HIV-1 latency. Annu Rev Pharmacol Toxicol 51:397-418 |
| Margolis, David M (2011) Eradication therapies for HIV Infection: time to begin again. AIDS Res Hum Retroviruses 27:347-53 |
| Denton, Paul W; García, J Víctor (2011) Humanized mouse models of HIV infection. AIDS Rev 13:135-48 |
| Margolis, David M (2011) Histone deacetylase inhibitors and HIV latency. Curr Opin HIV AIDS 6:25-9 |
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