The lungs remain a frequent target of HIV-related disease, although the mechanism(s) accounting for this increased susceptability are poorly understood. Alveolar macrophages (AM) are the predominant immune cell in the lungs, and serve a central role in mediating an effective """"""""first-line"""""""" host response to infectious challenge. AM are infected with HIV, but evidence for effector cell dysfunction remains controversial. Preliminary data in this application demonstrate that HIV-1 infection impairs mannose receptor-mediated phagocytosis of P. carinii, an important pulmonary pathogen in the HIV+ host. The macrophage mannose receptor is a prototype of a host defense surface protein of innate immunity which mediates recognition of specific carbohydrate moities expressed on the surface of pathogens. In the context of AIDS-related opportunistic infections, such pathogens include P. carinii, M. tuberculosis, MAC and C. neoformans. The Central Hypothesis is that HIV-1 and associated lung specific-factors dysregulate AM innate immune defense function, which in the setting of CD4+ T-lymphocyte depletion, predisposes the host to opportunistic lung infections. The goal of this project is to define the mechanism(s) underlying pulmonary innate immune cell dysregulation using the AM mannose receptor as the prototypic receptor of macrophage innate immunity. To test this hypothesis, experiments will address these Specific Aims: number 1) to characterize the expression and function of the cell membrane associated mannose receptor (mMR) comparing alveolar macrophages (AM) from healthy individuals to asymptomatic HIV-infected persons at high or low clinical risk for opportunistic pulmonary infections, and correlate with HIV-1 RNA and proviral DNA expression in the alveolar airspace; number 2) examine the mechanism of impaired mMR-mediated phagocytosis in AM in HIV-infected individuals by investigating the effects of in vitro HIV-1 infection, and the influence of specific exogenous and AAV vector-transduced structural and regulatory HIV-1 proteins on AM from healthy individuals; number 3) define the mMR-mediated signal transduction pathways comparing AM from healthy to HIV-infected individuals, and examine the influence of HIV-1 infection and HIV-1 gene products on Rho GTPase (Cdc42, Rac and Rho) and NF-kappaB/I-kappaB activity. Defining specific abnormalities in AM innate function will provide a rational basis for developing novel agents to augment local immune function, which could reduce the incidence or severity of pulmonary infections in patients with AIDS.
Showing the most recent 10 out of 16 publications
