Since the advent of potent combination antiretroviral therapy in the mid-1990s, improvements in its safety and tolerability and the emergence of new agents and classes has simplified treatment of HIV and made treatment success more likely. Our understanding of both the degree of treatment adherence needed to maintain long-term virological suppression and the pathophysiology of some of the major adverse events associated with HIV infection and therapy has improved. Anti-retroviral drugs targeting HIV encoded enzymes have slowed the death rate from AIDS but to date no effective vaccines have been developed and there is no practical cure. Today it is widely believed that the success in HIV-1 treatment will require targeting of other HIV and/or host cellular proteins. HIV-1 transcription is the most promising stage for which no drugs exist. Transcription is at the heart of regulating HIV-1 latency and, therefore, utilizing inhibitors that can target this promoter is significant. In fact, if an effectve inhibitor of HIV transcription was developed it could be considered a functional cure for AIDS. The long-term goal of our research is to understand how expression of the HIV-1 genome can be inhibited during active and latent infection. Our short term goals will be directed toward understanding mechanistic details of how a cdk9 inhibitor is able to selectively inhibit HIV -1 promoter. Our hypothesis is that understanding how Tat interfaces with a small form of P-TEFb, that is present only in HIV-1 infected cells, will provide targets for developing better antivirals that will block HIV-1 gene expression. The objective of this project is to elucidate the mechanisms used by a cdk9 inhibitor that can effectively maintain a quiescent transcriptional state in latently infected T cells. Our rationale for these studies is based on mounting preliminar data demonstrating the presence of unique P-TEFb complex in infected cells and its inhibition using latent cell systems and animal models.
The aims i nclude: defining mechanism of inhibition using in vitro transcription assay to define targets of Tat-specific P-TEFb (cdk9/T1) complex on the chromatin HIV DNA with our inhibitor and in vivo studies that will assess any cellular toxicity Assays will be utilized to define any potential side effects; and the effect of CR8#13 on HIV-1 latent models as well as humanized mouse NSG model. Collectively, these studies will define how CR8#13 can potentially contribute to long lasting transcriptional memory (i.e., methylation of the promoter) and suppression of virus in humans.
The current proposal is a novel and new approach to inhibit HIV in an epigenetically stable complex that could assist in the cure of AIDS. The methods utilized in this proposal are novel and range from in vitro to in vivo experimentations.
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