Disseminated Mycobacterium avium complex (MAC) infection is the most common bacterial opportunistic complication in patients with AIDS. Concern for emergence of MAC resistance to macrolides, inability to determine who is at risk for disseminated MAC disease, and whether potent anti-retroviral therapy will change approaches to treatment and prophylaxis for MAC, necessitate further study of the immunopathogenesis of MAC in HIV-infected patients. Colonization of gastrointestinal and pulmonary tracts precedes invasion and dissemination of MAC bacilli. Host defense to MAC disease require both CD4+ T cells and monoculear phagocytes. Mononuclear phagocytes from HIV-infected persons perform equally well compared to HIV-uninfected persons when tested in vitro, yet fail in vivo to control MAC. The in vivo immune defect in HIV-1 infected persons favoring MAC infection are poorly understood. In this proposal, investigators at Case Western Reserve University (CWRU) and University of California at San Diego (UCSD) combine expertise in clinical trials and basic immunology of MAC to investigate the immunopathogenesis of MAC in HIV-1 infected person.
The specific aims are: 1) To determine if serum markers of immune cell activation (neopterin, beta-2 microglobulin), and cytokine milieu (IL-6, TNF-alpha, TNF-alphaR, IL-2R, IFN-gama, IL-10) in HIV-1 infected persons can be used to predict dissemination of MAC infection, by analying in a case control study of serial serum samples collected in the azithromycin/rifabutin prophylaxis trial (669 subjects with 101 incident case of MAC). 2. To determine MAC specific function of CD4+ T cell in HIV-1 infected persons with MAC, who have reconstitution of CD4+ T cell number by anti-retroviral therapy. 3. To determine if in vivo selection of MAC strains is the result of differential induction and responsiveness to cytokines (IL-10, IL-6, TNF-alpha, IL-1alpha, TGF-beta, GM-CSF) produced by mononuclear phagocytes. These studies will take advantage of the ACTU units at CWRU and UCSD, and the Cytokine Core Facility of the Center for AIDS Research at CWRU and viral quantitation at UCSD. The findings of these studies will provide insight into the immunopathogenesis of disseminated MAC, necessary for the development of new diagnostic and therapeutic approaches to this disease.
