ALVEOLAR MACROPHAGE HOST DEFENSES

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Pulmonary infections are a major cause of the morbidity and mortality associated with infection by human immunodeficiency virus-1 (HIV-1). Based on the knowledge that alveolar macrophages (AM) play a central role in pulmonary host defenses, and that HIV-1 can infect AM, the underlying thesis of this proposal is that inherited and acquired host factors that influence the manner in which AM interact with HIV-1 are major determinants, directly and/or indirectly, of the dysfunction of pulmonary host defenses that is associated with HIV-1 infection. In this context, our goals are to understand the inherited and acquired host factors that modify the biology of HIV-1 interaction with human AM, to study mechanisms by which HIV-1 infection of AM lead to T-cell depletion in the lung, and to examine how the interaction of HIV-l and AM may be interrupted by modifying the intracellular and/or extracellular environment of the AM. Capitalizing on the recent discovery that chemokine receptors serve as co- receptors for HIV-1, and strategies to efficiently modify the genetic repertoire of human AM using replication deficient, recombinant adenovirus (Ad) vectors, we propose to use a panel of primary HIV-1 isolates for phenotype and co-receptor usage, and a characterized cohort of normal donors to serve as a source of AM, to evaluate: (1) co-receptor usage on AM from different individuals by HIV-1 isolates with different phenotypes; (2) the association of HIV-1 infection of AM with AM-induced apoptosis of T-cells via the fas ligand-fas pathway; and (3) modulation of the genetic repertoire of AM relevant to.co-receptor expression and HIV-l infection. This proposal represents a unique collaboration of two groups with diverse skills: the expertise of the Cornell University Medical College group regarding AM biology and Ad vector-mediated gene transfer; the expertise of the Aaron Diamond AIDS Research Center regarding HIV-1 biology; and the combined access of our two groups to the relevant biologic reagents and study populations.