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. ? ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Peavy, Hannah H
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University of Pittsburgh
Schools of Medicine
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Morris, Alison; Paulson, Joseph N; Talukder, Hisham et al. (2016) Longitudinal analysis of the lung microbiota of cynomolgous macaques during long-term SHIV infection. Microbiome 4:38
Kling, Heather M; Shipley, Timothy W; Guyach, Siobhan et al. (2014) Trimethoprim-sulfamethoxazole treatment does not reverse obstructive pulmonary changes in pneumocystis-colonized nonhuman primates with SHIV infection. J Acquir Immune Defic Syndr 65:381-9
George, M Patricia; Champion, Hunter C; Simon, Marc et al. (2013) Physiologic changes in a nonhuman primate model of HIV-associated pulmonary arterial hypertension. Am J Respir Cell Mol Biol 48:374-81
Morris, Alison; Norris, Karen A (2012) Colonization by Pneumocystis jirovecii and its role in disease. Clin Microbiol Rev 25:297-317
Kling, Heather M; Shipley, Timothy W; Norris, Karen A (2011) Alterations in peripheral blood B-cell populations in SHIV89.6P-infected macaques (Macacca fascicularis). Comp Med 61:269-77
Norris, Karen A; Morris, Alison (2011) Pneumocystis infection and the pathogenesis of chronic obstructive pulmonary disease. Immunol Res 50:175-80
Kling, Heather M; Shipley, Timothy W; Patil, Sangita P et al. (2010) Relationship of Pneumocystis jiroveci humoral immunity to prevention of colonization and chronic obstructive pulmonary disease in a primate model of HIV infection. Infect Immun 78:4320-30
Shipley, Timothy W; Kling, Heather M; Morris, Alison et al. (2010) Persistent pneumocystis colonization leads to the development of chronic obstructive pulmonary disease in a nonhuman primate model of AIDS. J Infect Dis 202:302-12
Kling, Heather M; Shipley, Timothy W; Patil, Sangita et al. (2009) Pneumocystis colonization in immunocompetent and simian immunodeficiency virus-infected cynomolgus macaques. J Infect Dis 199:89-96
Morris, Alison; Sciurba, Frank C; Norris, Karen A (2008) Pneumocystis: a novel pathogen in chronic obstructive pulmonary disease? COPD 5:43-51

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