Despite the clinical success of antiretroviral therapy (ART), more people contract human immunodeficiency virus (HIV) infection daily than initiate ART. The difficulties of lifelong ART - particularly in the developing world - make the eradication of HIV imperative. But clearance of a retroviral infection for patients on ART is a herculean task. While much is known about HIV persistence despite ART, many puzzles remain. New tools to address latent infection must replace the paradigms and models used to develop ART. Existing cellular and animal models that represent HIV latency in vivo require further development, and while latent provirus can be purged in the laboratory, a testable, comprehensive therapeutic strategy is not at hand. Therefore we propose the Martin Delaney Collaboratory to Eradicate HIV-1 Infection, a close collaboration of 21 exceptional investigators who have collectively led the field of HIV latency over the last 10 years. To maximize success, we will work across four areas of research to develop the infrastructure and systems needed to define eradication therapies, identify new molecules with therapeutic potential and provide a proof-of-concept for a small molecule based eradication strategy in animal models. Objective 1 will identify the molecular mechanisms underlying viral persistence and latency;Objective 2 will identify drug candidates and therapeutic strategies to reduce the latent viral pool;Objective 3 will establish informative animal model systems to evaluate latency and test therapeutic strategies;and finally. Objective 4 will perform studies in humans to delineate the basis for viral persistence. Three cores will assist research projects with pharmacology, molecular assays, and sequence and expression analysis. An administrative core will assure coordination, and maintain the focus of this experienced and potent group towards translational product development. As a group, we are committed to pooling our resources and expertise to transcend the normal constraints of academic research. Of note, the expertise and durable commitment of Merck Research Laboratories will be critical to delivering therapeutic advances. We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection.
Despite the success of antiretroviral therapy (ART) in decreasing mortality for HlV-1-infected patients, ART has not cured the disease. A persistent viral reservoir in the T cells of HIV patients receiving potent ART is a significant barrier preventing an HIV cure. Including scientists from eight universities and Merck Research Laboratories, the Martin Delaney Collaboratory will seek to eradicate HIV infection by developing and testing therapies, capable of eventually being tested clinically, that will permanently destroy the viral reservoir.
|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|
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