The assays that have been applied to measure the latent reservoir in studies performed to date have been imprecise, in some cases non-specific, and in all cases near the threshold of detection for specimens obtained from subjects effectively treated with antiretroviral therapy. A successful Collaboratory effort to eradicate the latent reservoir must have assays available that can reliably quantify this reservoir and measure reductions in its size. In Project 4.1, superior assays in development for integrated viral DNA and for viral infectivity will be refined and validated for HIV, and then applied to both the SIV and RT-SHIV macaque models. They will then be applied to in vitro models of latency and to cells and tissues obtained from infected macaques and HIV-infected study subjects, as part of other Collaboratory research projects. Microfluidic applications to these assays will address the question of the representativeness of the proviral reservoir for replication-competent virus and try to explain some of the mechanisms for replication in competent virus. The presence of HIV DNA and infectivity in blood macrophages, as a potential reservoir, will also be examined. These studies to improve measurements of the latent reservoir and interventions to purge it will involve close interactions and the exchange of methods and materials with several of the project and core Collaboratory investigators.
Assays are inadequate to measure the latent reservoir and the effect of treatments to reduce it. This project with refine innovative new assays to address this problem and then apply them to projects in the Collaboratory. In addition with innovative microfluidic technology this project will address the relationship of HIV DNA integrated in host cells and infectious virus in this latent 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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