HIV-associated immune suppression contributes to increased colonization of commensal and opportunistic pathogens in the mouth, leading to oral complications in many HIV-infected patients. With the increasing number of HIV cases and longer life-expectancy of HIV patients, HIV-associated periodontal disease is expanding as a major health care issue. We hypothesize that HIV infection of tissue resident macrophages contribute directly to this compromise in oralpharyngeal immunity and enhanced host sensitivity to periodontal pathogens, such as the anaerobic bacterium Porphyromonas gingivalis. We are proposing to employ tissue resident macrophages from the oral cavity, specifically palatine tonsils, as a tractable primary cell model to study how HIV impacts macrophage function and associated oral pathogenesis. In addition, we propose determining signals that lead to epigenetic regulation in the context of the primary macrophages. An important aspect of this proposal is our ability to access clinical samples from patients with HIV and our previous experience in providing them with dental care. Using this cohort and our collective expertise, we will perform studies that complement our in vitro studies by characterizing macrophages and cytokines that are present in the oral cavities of HIV infected and control individuals. Upon completion of these studies, we expect to have novel insights into how PD infections contribute to a microenvironment that facilitates HIV replication, inflammation and further periodontal tissue destruction, directly contributing to HIV-associated oral pathogenesis.
Oral complications develop in most HIV-infected patients. A major goal of this proposal is to understand how HIV-infected macrophages directly contribute to dysregulated inflammation in the mouth, promoting tissue damage and a favorable microenvironment for HIV-1 replication.
|Agosto, Luis M; Hirnet, Juliane B; Michaels, Daniel H et al. (2016) Porphyromonas gingivalis-mediated signaling through TLR4 mediates persistent HIV infection of primary macrophages. Virology 499:72-81|
|Papadopoulos, G; Shaik-Dasthagirisaheb, Y B; Huang, N et al. (2016) Immunologic environment influences macrophage response to Porphyromonas gingivalis. Mol Oral Microbiol :|
|Huang, N; Shaik-Dasthagirisaheb, Y B; LaValley, M P et al. (2015) Liver X receptors contribute to periodontal pathogen-elicited inflammation and oral bone loss. Mol Oral Microbiol 30:438-50|
|Kaczmarek Michaels, Katarzyna; Natarajan, Malini; Euler, Zelda et al. (2015) Blimp-1, an intrinsic factor that represses HIV-1 proviral transcription in memory CD4+ T cells. J Immunol 194:3267-74|
|Kaczmarek Michaels, Katarzyna; Wolschendorf, Frank; Schiralli Lester, Gillian M et al. (2015) RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters. Virology 486:7-14|
|Collins, Matthew H; Henderson, Andrew J (2014) Transcriptional regulation and T cell exhaustion. Curr Opin HIV AIDS 9:459-63|