The benefits of antiretroviral therapy (ART) to HIV-infected patients are significant. However, ART interruption is coupled with a rapid rebound in plasma viremia. This rebound signifies the ultimate challenge surrounding ART - its inability to completely eradicate HIV. Understanding the mechanisms by which the virus is able to persist in the face of ART is necessary in order to identify strategies that may interrupt viral persistence and ultimately lead to virus eradication. There is a definite need for the implementation of in vivo models where these mechanisms can be elucidated and induction/eradication interventions aimed at virus eradication can be evaluated. Novel humanized mice (bone marrow-liver-thymus or BLT mice) developed in our laboratory could serve effectively in this capacity. Humanized BLT mice exhibit systemic reconstitution (including in the gut and vaginal mucosa) with a complete and functional human immune system. The functionality and usefulness of BLT mice in the study of HIV persistence and eradication will become evident when the following aims are completed, wherein the parameters of viral persistence will be established and novel eradication approaches will be tested. The long-term goal of our project is to develop and implement an in vivo animal model in which novel protocols for HIV-1 eradication can be evaluated. This project will first compare different drug regimens aimed at establishing durable suppression of viremia in humanized BLT mice to allow the detailed study of persistence and latency. We will then establish the sites of residual virus infection that persist despite ART. After the establishment of this model, this project will evaluate the effect of novel reagents to disrupt latency with the ultimate long-term goal of establishing virus eradication. Our goals will be achieved by pursuing the following specific aims:
Specific Aim 1 : To establish an optimal drug regimen for the durable suppression of viremia in humanized BLT mice.
Specific Aim 2 : To characterize the nature and the anatomical location of viral reservoirs which persist in BLT mice undergoing ART.
Specific Aim 3 : To characterize the effect of select induction therapeutic interventions for their ability to eradicate virus from infected BLT mice, by significantly delaying or preventing rebound after discontinuation of antiretroviral therapy. HIV eradication is a daunting task that has proven to be extremely difficult to achieve in patients. The significance of this project rests on its goal: to develop and implement a novel in vivo model in which eradication approaches aimed at the development of a potential "cure" for HIV infection can be evaluated in vivo prior to clinical implementation.
The research proposed in this application is innovative, in our opinion, because it represents a new and substantially different way of addressing a most important step in the discovery process towards a cure for HIV/AIDS: the development of validated in vivo systems for the evaluation of HIV eradication strategies. In essence, our approach of developing the humanized BLT model to study HIV latency and eradication represents an important departure from the status quo in the field with the significant potential of enabling new opportunities for the translation of laboratory observations into clinical implementation.
|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