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.
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