"HIV-1 pathogenesis and macrophage dysfunction"
Following HIV infection, progression to AIDS is associated with a generalized immune dysregulation that becomes manifested through a number of opportunistic infections and malignancies. This immune dysfunction occurs in numerous immune cell types, including CD4+ T-cells, CD8+ T-cells, B-cells, and macrophages. In macrophages, HIV infection has been shown to impair functional responses to pathogens including phagocytosis, production of reactive oxygen species, and cytokine production, ultimately impairing their ability to identify and kill pathogenic bacteria, like Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. The goal of this proposal is to investigate how HIV disease pathogenesis impacts monocyte/macrophage functional response to Mtb. Indeed, this pathogen is clinically relevant as nearly one-half of worldwide AIDS-related deaths are due to complications of a tuberculosis infection. The first aim of this training grant is to assess Mtb induced functional responses of monocytes/macrophages obtained from the peripheral blood of hosts of pathogenic HIV and nonpathogenic SIV infections. The second aim is to quantify the impact that HIV or SIV infection has on the ability of Mtb to replicate in host monocytes/macrophages. Our overall hypothesis is that monocytes/macrophages from HIV+ patients will be impaired in their ability to carry out functional responses essential to Mtb killing compared to uninfected cells and cells taken from SIV natural host monkey species (i.e. sooty mangabeys) that do not exhibit clinical signs of sAIDS. Understanding how pathogenic HIV and nonpathogenic SIV infections impact monocyte/macrophage function has the potential to lead to the development of new therapeutic approaches to combat opportunistic infections, like Mtb, that exploit the immunocompromised host.