Latently infected, quiescent CD4 T cells represent a central obstacle to eradication of HIV-1. Major hurdles are the low frequencies of latently infected cells in peripheral blood and the lack of known phenotypic markers that can distinguish them from uninfected ones. These impediments have prompted the development of in vitro cell models of latency, which. Such models allow manipulation of cellular and viral characteristics to gain a mechanistic understanding of how latency is established and regulated. However, no single experimental system of HIV latency is perceived to completely recapitulate the biology ofthe latent viral reservoir in vivo. This is mainly because (a) the mechanisms for establishment of latency by HIV are multiple;and (b) the types of cells harboring latent reservoirs are also multiple. A wealth of knowledge has been gained regarding how specific stimuli (e.g. activation/differentiation, homeostatic proliferation, cytokines) and viral factors (e.g. integration site, Tat-driven expression) influence the dynamics of latent reservoirs in experimental systems. Project 2.2 will perform """"""""secondary level"""""""" characterization of novel small molecule compounds and combinations that have been identified to induce HIV transcription through primary screening by Dr. Hazuda's group in Project 2.1.
In Aims 1 and 2, we propose to use a panel of wellcharacterized primary cell systems and one Jurkat-based cell line to validate candidate drug compounds.
A third Aim will be the development of additional primary cell models to enable the study of HIV-1 latency in other relevant cell types not previously explored ex vivo (e.g. transitional memory T cells and macrophages). Drugs and combinations that are active in at least one ofthe primary culture systems, without showing overt toxicity or induction of cellular activation/proliferation, will be moved to subsequent phases of characterization and development within this Collaborative program. This will include detailed mechanistic studies (Objective 1), testing for activity in humanized mice and non-human primates (Objective 3) and in patient cells ex vivo (Objective 4). Our ultimate goal is to identify novel drugs and combinations that will have a high probability for success in activating HIV latent viruses when applied in patients.
Within the Deianey Collaboratory program, the overall goal of Project 2.2 is the application of in vitro primary cell culture systems to identify new drug-like substances and combinations that will activate latent HIV in biological systems, prior to studies in animals and humans. A second aspect of these studies is to begin to identify the mechanims of action of such drugs, such that future studies can focus on identification of novel cellular targets and pathways, which will broaden of the scope of therapeutic possibilities in the near future.
|Davis, Zachary B; Cogswell, Andrew; Scott, Hamish et al. (2016) A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells. PLoS Pathog 12:e1005421|
|Imaz, Arkaitz; Martinez-Picado, Javier; NiubÃ³, Jordi et al. (2016) HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen. J Infect Dis 214:1512-1519|
|Honeycutt, Jenna B; Wahl, Angela; Baker, Caroline et al. (2016) Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest 126:1353-66|
|Tokarev, Andrey; Stoneham, Charlotte; Lewinski, Mary K et al. (2016) Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1. J Virol 90:2486-502|
|Victor Garcia, J (2016) Humanized mice for HIV and AIDS research. Curr Opin Virol 19:56-64|
|Smith, Davey M; Nakazawa, Masato; Freeman, Michael L et al. (2016) Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment. Clin Infect Dis 63:1517-1524|
|Gianella, Sara; Anderson, Christy M; Var, Susanna R et al. (2016) Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection. J Virol 90:3944-52|
|Garcia, J Victor (2016) In vivo platforms for analysis of HIV persistence and eradication. J Clin Invest 126:424-31|
|Lee, Sook-Kyung; Zhou, Shuntai; Baldoni, Pedro L et al. (2016) Quantification of the Latent HIV-1 Reservoir Using Ultra Deep Sequencing and Primer ID In A Viral Outgrowth Assay. J Acquir Immune Defic Syndr :|
|Wagner, Gabriel A; Chaillon, Antoine; Liu, Siqi et al. (2016) HIV-associated neurocognitive disorder is associated with HIV-1 dual infection. AIDS 30:2591-2597|
Showing the most recent 10 out of 187 publications