Pneumocystis pneumonia (PCP) remains an important cause of morbidity and mortality in HIV-infected patients. CD4+ T cells are critical to clearance of Pneumocystis (Pc), however the role of other immune effectors in controlling this infection or in promoting lung tissue injury is less clear. The presence PC in the lung induces an intense inflammatory response, but the physiologic significance of this response is not well understood, and HIV infection itself can result in inflammatory responses that may cause acute or chronic lung injury. We have developed a novel, non-human primate model of SIV and PC co-infection that closely represents the immune dysfunctions of AIDS, and we propose to use this model to study the interaction of SIV and PC to identify immune mediators that may be exploited to better control PC infection and ameliorate lung injury.
The specific aims of this proposal are: 1) To test the hypothesis that the CD8 T cell-predominant lymphocytic alveolitis associated with PC in SIV-infected monkeys and the resultant inflammatory response leads to worsening SIV infection and progression to AIDS. The specificity and function of the infiltrating cells will be determined, and we will determine whether this response has a protective or detrimental effect on disease progression; 2) To test the hypothesis that specific inflammatory responses associated with prolonged PC colonization and infection in SIV-infected monkeys leads to chronic lung injury and worsening pulmonary function. We will measure cellular composition and inflammatory mediators in bronchoalveolar lavage fluid and correlate changes in local immune responses with alterations in lung function. In addition, we will test the effect of local delivery of interleukin-10 in control of lung inflammation and injury; 3) To test the hypothesis that a local humoral response contributes to clearance of PC in SIV-infected monkeys. We will characterize the nature and function of anti-Pc antibodies in serial BAL and plasma samples from SIV/Pc inoculated animals and test the effect of previous exposure to PC antigens and Th2 skewing of the response on the capacity of SIV/Pc-inoculated animals to control the infection. These studies will begin to identify both protective and detrimental immune responses to PC in the context of AIDS immunosuppression and help to characterize novel avenues for immunotherapy and prevention of immune-mediated lung injury in AIDS-associated PC infection. ? ? ? ?
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