There is a significant unmet need to develop therapeutics that could cure HIV infection by eliminating reservoir cells where the virus resides during antiretroviral therapy [ART]. This need persists because of gaps in knowledge of how HIV maintains persistent latent infection of reservoir cells. These gaps represent an important problem because until they are filled a cure for HIV remains impossible. The long term goal is to more completely understand host mechanisms that regulate HIV latency versus active replication. The immediate objective of this application is to prove that pharmacologic inhibitors of dual specificity tyrosine- phosphorylation-regulated kinase 1A [DYRK1A] allow optimal reactivation of latent HIV from CD4 T cells. To achieve this objective, a combination of latently HIV-infected cell lines and primary CD4 T cells will be utilized to investigate the role of DYRK1A in maintaining HIV latency. The central hypothesis is that DYRK1A facilitates HIV latency by negatively regulating host transcription factors that drive the HIV LTR promoter. This hypothesis is based upon preliminary studies performed in the applicant's laboratory demonstrating that the DYRK1A inhibitor harmine boosts the efficacy of existing latency reversing agents [LRAs] and enhances LRA-induced NFAT activity. Furthermore, knockdown of DYRK1A mimics the effects of harmine. A secondary hypothesis is that DYRK1A inhibits antigen-induced activation of CD8 T cells, thus contributing to the failure of patient CD8 T cells to kill HIV reservoir cells wherei HIV replication has been triggered by LRAs. We demonstrate that harmine enhances antigen-induced CD8 T cell activation. Thus, our pharmacologic approach is entirely novel because it simultaneously improves reactivation of latent HIV and improves activity of the CD8 effector cells needed to kill off the HIV reservoir. The rationale for the proposed study is that understanding host mechanisms that regulate HIV latency and replication will lead to development of new drugs to maximize reactivation of latent HIV and to maximize death of reservoir cells that carry HIV genomes. Guided by preliminary studies, the hypothesis will be objectively tested by pursuing three specific aims: 1) Establish the efficacy of DYRK1A inhibitors as anti-latency drugs; 2) Identify host transcription factors that are required for optimal HIV reactivation from latently-infected CD4 T cells; and 3) Establish the efficacy of DYRK1A inhibitors for enhancing death of reactivated HIV reservoir cells. The approach is innovative because it uses inhibitors of a specific host regulatory protein, DYRK1A, to better understand mechanisms that control HIV gene expression and viability of reservoir cells as well as CD8 T cell activation. The proposed research is significant because it is expected to advance a new class of anti-latency drugs (DYRK1A inhibitors) and to increase mechanistic understanding of HIV latency as a basis for new research based on expected outcomes. Ultimately, the knowledge gained from this work has the potential to support a combination therapeutic cure for HIV infection.

Public Health Relevance

The proposed research is relevant to public health because the discovery of host factors that regulate HIV latency and the identification of a new class of anti-latency drugs will increase understanding of the processes and mechanisms required to cure HIV infection. Thus, the research is relevant to part of the mission of the NIH to develop new approaches to reactivate/eradicate latent HIV infection as part of a comprehensive strategy to cure HIV/AIDS.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Conley, Tony J
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University of Florida
Schools of Medicine
United States
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