Redox Regulated HIV Expression in Alveolar Macrophages

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DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in Pulmonary and Critical Care Medicine. The principal investigator has completed a three year residency in Internal Medicine at the University of Maryland and a four year subspecialty training program in Pulmonary and Critical Care Medicine at Boston University (BU). He now seeks to develop his scientific skills of investigation into redox biology and HIV pathogenesis in the lung. Hardy Kornfeld, MD will mentor the principal investigator's development. He is an established investigator and an expert in the area of innate immunity and HIV dynamics in the lung. He has successfully trained graduate students and numerous fellows who are active in academic medicine. Expertise in the area of redox biology will be provided by the co-sponsor Jane Freedman, MD. A committee composed of senior investigators in the areas of redox, HIV and pulmonary biology will meet quarterly with the principal investigator to advise him on scientific and career matters. Research will focus on redox regulation of HIV-1 replication in human alveolar macrophage (AM). Preliminary studies demonstrate inhibition of HIV-1 by reactive oxygen intermediate (ROI) inhibitors at the transcriptional level. The effect of HIV-1 infection and viral proteins on AM production of ROI and reactive nitrogen intermediates (RNI) will be studied. This examination will be extended to naturally infected AM from seropositive individuals to examine the impact of hyperoxia and microbial challenge on redox regulated HIV- 1 replication in AM. The specific aims include: 1 characterizing the effect of HIV on the redox state of AM and its impact on HIV replication dynamics, 2) Determining the mechanism of ROI/RNI induced transcription of HIV, and 3) Determining whether HIV can be induced from naturally infected AM from seropositive patients by altering the redox state. These studies will be the first to analyze the effect of oxidative stress on HIV-1 replication in the human AM, a reservoir of persistent HIV-1 infection in the asymptomatic patient. The Pulmonary Center at BU and The Center for AIDS Research at UMass will provide customized training and outstanding interdisciplinary environments that will support the development of the principal investigators niche in lung biology and facilitate his transition to an independent investigator.