HIV targets both lymphocytes and macrophages as host cells. Most studies equate progression to AIDS solely as the loss of T cell surveillance. However, it has been suggested that because HIV parasitizes macrophages, the virus could impair the microbicidal capacity of the phagocyte directly. Exploiting novel assays for phagosomal maturation we have demonstrated that HIV infection diminishes the hydrolytic capacity of the phagosome and impairs superoxide production. Given the macrophage's role as the primary barrier against microbial invasion this will have serious consequences, particularly at mucosal surfaces such as the respiratory tract. In this study we propose to address the following 3 questions. 1. To what extent does HIV infection compromise the anti-microbial capacity of macrophages? HIV-infected, PBMC-derived macrophages will be subjected to a panel of physiological assays to determine the extent to which phagocyte function is impaired i.e. phagosome acidification, the acquisition of lysosomal hydrolases, the generation of reactive oxygen and nitrogen intermediates, and the capacity of the HIV-infected cells to limit growth of a panel of model bacterial pathogens. 2. Do alveolar macrophages from HIV-infected patients demonstrate similar subversion of phagocyte function? Following in vitro validation, these assays will be repeated on broncholavage cells from HIV-infected patients at the Queen Elizabeth Hospital in Malawi. In addition, samples will be acquired for electron microscopy and for immuno-electron microscopy, and total nucleic acid will be extracted for retrospective identification of possible co-infections. 3. How does HIV impair macrophage function and can this be reversed chemotherapeutically? a. We propose functional studies to determine how HIV modulates the microbicidal capacity of the phagosome. b. We will conduct high-throughput screens to identify small molecules that counteract the suppressive activity of HIV. c. We will assay these compounds for their ability to reverse the suppression of phagocyte function in alveolar macrophages from HIV-infected patients.
The progression to AIDS is almost universally correlated with the loss of immune surveillance. However, we have found that HIV-infected macrophages exhibit impaired phagosomal function that reduces their microbicidal capacity, thus directly increasing the likelihood of opportunistic infections. In a prospective clinical study on alveolar macrophages from HIV-infected patients we will parallel our in vitro experiments to pursue both the mechanism and the identification of compounds that reverse the HIV-mediated suppression of macrophage function.
|Jambo, Kondwani C; Tembo, Dumizulu L; Kamng'ona, Arox W et al. (2017) HIV-associated disruption of lung cytokine networks is incompletely restored in asymptomatic HIV-infected Malawian adults on antiretroviral therapy. ERJ Open Res 3:|
|Wilburn, Kaley M; Mwandumba, Henry C; Jambo, Kondwani C et al. (2016) Heterogeneous loss of HIV transcription and proviral DNA from 8E5/LAV lymphoblastic leukemia cells revealed by RNA FISH:FLOW analyses. Retrovirology 13:55|
|Dumas, Audrey; Lê-Bury, Gabrielle; Marie-Anaïs, Florence et al. (2015) The HIV-1 protein Vpr impairs phagosome maturation by controlling microtubule-dependent trafficking. J Cell Biol 211:359-72|
|Rylance, Jamie; Fullerton, Duncan G; Scriven, James et al. (2015) Household air pollution causes dose-dependent inflammation and altered phagocytosis in human macrophages. Am J Respir Cell Mol Biol 52:584-93|
|Podinovskaia, Maria; Russell, David G (2015) Detection and quantification of microbial manipulation of phagosomal function. Methods Cell Biol 126:305-29|
|Jambo, Kondwani C; Banda, Dominic H; Afran, Louise et al. (2014) Asymptomatic HIV-infected individuals on antiretroviral therapy exhibit impaired lung CD4(+) T-cell responses to mycobacteria. Am J Respir Crit Care Med 190:938-47|
|Jambo, K C; Banda, D H; Kankwatira, A M et al. (2014) Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function. Mucosal Immunol 7:1116-26|
|Russell, David G (2011) Mycobacterium tuberculosis and the intimate discourse of a chronic infection. Immunol Rev 240:252-68|
|Russell, David G (2011) The galvanizing of Mycobacterium tuberculosis: an antimicrobial mechanism. Cell Host Microbe 10:181-3|
|Russell, David G; Barry 3rd, Clifton E; Flynn, JoAnne L (2010) Tuberculosis: what we don't know can, and does, hurt us. Science 328:852-6|
Showing the most recent 10 out of 11 publications