Life-threatening opportunistic pneumonia frequently complicates HIV-1 infection, although the underlying predisposing mechanisms remain poorly understood. Pulmonary innate immune host defense is mediated in part by effector cells such as alveolar macrophages (AM) which recognize pathogen-associated molecular patterns (PAMP) through specific surface receptors such as complement receptors, scavenger receptors, beta-glucan receptor, Toll-like and LPS receptor (CD 14), and mannose receptor. Previous data from this laboratory demonstrated that HIV-1 infection impairs AM mannose receptor-mediated phagocytic function which may in part contribute to host susceptibility to opportunistic pulmonary pathogens such as P. carinii, C. neoformans, and M. tuberculosis. Recognizing the importance of NF-kB/I-kB signaling pathway in host cell response to infectious challenge, preliminary data now show that HIV invokes a specific alteration in mannose receptor-mediated NF-KB signaling pathway. In this proposal, we will further define the influence of HIV on AM innate immune receptor function focusing on NF-kB/I-kB signal pathway. The central hypothesis for this proposal is that HIV alters AM innate receptor-mediated NF-kB/I-KB signal transduction pathways, which may impair an effective innate immune response to pulmonary pathogen challenge and contribute to host susceptibility to opportunistic infections. Employing AM from healthy individuals, these studies will elucidate the mechanism of HIV-mediated NF-kB/I-KB signal dysregulation by focusing on the following specific aims:
Specific Aim #1 : Define the influence and specificity of HIV-1 on AM mannose receptor-mediated NF-KB nuclear translocation.
Specific Aim #2 : Examine the role of specific HIV-1 gene products on mannose receptor-mediated NF-kB signaling (using exogenous HIV-1 proteins and AAV vector delivery of env, tat, vpr, nef).
Specific Aim #3 : Define the level of HIV-mediated dysregulation of mannose receptor-mediated NF-kB signaling by examining upstream signaling molecule Protein Kinase C, Rho GTPase and PI-3 kinase. Defining specific impairments in AM innate function will provide a rational basis for developing novel agents to augment local immune function, which could reduce the incidence of pulmonary infections in patients with AIDS.
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