Macrophages are sentinel cells that play a pivotal role in a broad range of innate and adaptive immune responses. Macrophages can be infected by HIV-1 and because these are long-lived cells and are resistant to the cytopathic effects of virus infection, contribute significantly to the virus reservoir throughout the course of the disease. Macrophages are present ubiquitously in all tissues and can disseminate virus to CD4+ T cells across cell-to-cell junctions with high efficiency. In this proposal, we will test the hypothesis tat establishment of productive infection in macrophages by HIV-1 and de novo viral protein expression triggers type I IFN-dependent pro-inflammatory responses. Using a proviral mutagenesis and expression strategy, we will identify the viral determinants that are necessary for inducing innate responses. We will utilize immuno-affinity purification and mass spectrometry approaches to identify the host factor(s) that detects these pathogen determinants and the signaling cascades that are triggered upon engagement of the viral determinants by this yet to be identified host factor. Finally, we will determine if induction of innate responses enhances expression of interferon-stimulated genes, such as CD169, that are subverted by HIV-1 to facilitate virus spread to CD4+ T cells across infectious synapses, a macrophage-dependent mechanism of systemic virus dissemination.

Public Health Relevance

Although HIV-1 replication in vivo can be suppressed to very low or undetectable levels in infected individuals by HAART, chronic inflammation persists and has significant negative consequences for the health of the infected individual. Hence, defining the mechanisms for persistent inflammation in the context of HAART is a key question that remains unanswered. In this proposal, we will identify the molecular mechanisms by which productive HIV-1 infection induces immune activation in macrophages.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Mcdonald, David Joseph
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Boston University
Schools of Medicine
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