Highly active antiretroviral therapy (HAART), consisting of potent combinations of antiretroviral drugs, has been a major advance in the treatment of HIV-1 infection and AIDS. However, these regimens do not eradicate the virus which can establish latency. A proposed approach for eradication involves induction of the virus from latent reservoirs while continuing H/ ART. Simultaneous HAART during this induction treatment would inhibit the spread of virus released from reservoirs. This approach, designated induction/eradication therapy, is based on agents that activate viral gene expression. We are using a nonhuman primate model (RT-SHIV) that recapitulates many of the features of HIV-1 infection in humans, including suppression of virus load by H/ ART. Importantly, this model enables rigorous assessment of the potential clinical impact of treatment regimens by allowing measurement of viral rebound upon cessation of treatment with both HAART and viral activators. The hypothesis is that pharmacologic induction of latent virus in RT-SHIV infected macaques under HAART will either eliminate virus or substantially reduce levels of virus and thereby produce a drug-free remission. We will first focus on suborylanilide hydroxamic acid (SAHA, Vorinostat), a histone deacetylase (HDAC) inhibitor which influences chromatin remodeling atthe viral promoter. Synergistic effects between HDAC inhibitors and small molecule activators of specific transcription pathways have been used for induction of virus in cell culture models of HIV latency. Accordingly, we will incorporate other viral inducers (e.g., bryostatin - an activator of protein kinase C and the NF-kB pathway) to determine whether an optimal induction therapy should involve a combination of inducers that act through different mechanisms regulating viral transcription.
Aim 1 : To test an induction/eradication therapy based on intensified-HAART and SAHA plus bryostatin in the RTSHlV/ macaque model.
Aim 2 : To analyze the mechanism(s) of induction/eradication therapy in the macaque model.
Aim 3 : To test novel viral induction compounds and approaches identified in the HIV Collaboratory.
Aim 4 : To evaluate the efficacy of an induction regimen given together with HAART very early after RT-SHIV infection of macaques.
The studies on induction/eradication therapies in the RT-SHIV/macaque model for HIV/AIDS will directly contribute to identification of the range of cells and tissues harboring latent proviruses, dissection of molecular mechanisms underlying HIV-1 latency and persistence, and discovery and evaluation of new compounds and strategies for successfully purging the virus from the latent reservoirs or for reducing latent/persistent virus and thereby establishing a period of drug-free remission.
|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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