Antiretroviral medications currently represent the only effective means for controlling HIV pathogenesis, but existing drug regimens cannot fully stop viral replication in vivo. It is thus critical to identify physiologic processes that support residual HIV replication during highly active antiretroviral therapy (HAART). Recent data indicate that high levels of activity in the sympathetic division of the autonomic nervous system (ANS) represent an in vivo risk factor for elevated plasma viral load in untreated patients and those receiving HAART. The nervous system has long been known to regulate the activity of certain viral pathogens (e.g., herpes viruses), but little is known about its impact on lentiviruses such as HIV or SIV. ANS neurons innervate the lymphoid organs that serve as major sites of HIV-1 replication in vivo, and T lymphocytes bear beta adrenoreceptors that allow neural modulation of cellular activation, cytokine production, and cell trafficking. In previous studies, we found that the ANS neurotransmitter norepinephrine accelerates HIV-1 replication in vitro by altering cellular vulnerability to infection and enhancing viral gene expression. The proposed studies seek to define the molecular mechanisms of these effects. Specifically, these studies aim to: 1. Identify transcriptional mediators of ANS-induced HIV-1 gene expression. 2. Define ANS effects on soluble factors that modulate HIV-1 replication. 3. Assess interactions between ANS neurons and HIV/SIV replication in lymphoid tissues. These studies will establish a virologic framework for interventions aimed at blocking ANS support of residual HIV replication during HAART. Such interventions would enhance the efficacy of current antiretroviral treatment regimens by opposing physiologic processes that support ongoing pathogenesis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS and Related Research 8 (AARR)
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Young, Janet M
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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