One third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and over 10 million are co-infected with human immunodeficiency virus (HIV). Latent Mtb infection (LTBI) represents immune containment, however HIV infection increases the risk of reactivation of LTBI from a 5-10% lifetime risk in HIV- uninfected individuals to a 10% annual risk in HIV-positive individuals. HIV-associated dysregulation of innate immunity and impairment of adaptive immunity by depletion of CD4 T helper cells likely contribute to loss of immune control of LTBI and progression to TB disease in HIV co-infected individuals. However, the parameters of immune control of LTBI that are perturbed in the setting of HIV co-infection have not been defined. Studies of Mtb infection in humans and animal models have demonstrated that both innate and adaptive immunity, particularly T cells, are critical for immune control of LTBI. Interestingly, recent evidence indicates innate immune cells play an important role in modulating antigen-specific T cell responses. Natural killer (NK) cells have been shown to modulate antigen-specific T cells by direct mechanisms, such as lysis of activated and/or antigen-specific CD4 and CD8 T cells, and indirect mechanisms, such as editing dendritic cell populations that prime effector T cell responses, and limiting the capacity of antigen presenting cells to stimulate antigen- specific T cell proliferation. Thus, innate immune cells can shape the profiles of antigen-specific T cell responses to a pathogen. The focus of this proposal is to examine how the innate immune response modulates Mtb-specific T cell immunity and determine how the regulatory pathways linking innate and adaptive immunity to Mtb are perturbed in the setting of HIV co-infection. We propose to test the hypotheses that (1) NK cells modulate the phenotype and functional profile of Mtb-specific memory T cells, and (2) that co-infection with HIV perturbs NK cell-mediated regulation of Mtb-specific memory T cell responses by promoting NK cell lysis of Mtb-specific CD4 and CD8 T cells, thereby contributing to loss of immune control of LTBI and increased risk of progression to TB disease in HIV/Mtb co-infected individuals. We propose to (1) define the phenotypic profiles, functional capacities, and NK cell receptor genotypes in persons with LTBI and HIV co-infection; (2) determine the relationship between NK cell profiles and the phenotype and function of Mtb-specific CD4 and CD8 T cell responses; and (3) define the direct and indirect mechanisms whereby NK cells modulate Mtb-specific CD4 and CD8 T cell immunity in LTBI, and how the mechanisms of cross-talk between NK cells and Mtb-specific T cells are dysregulated in the setting of HIV co-infection. Defining immune pathways involved in the generation, maintenance, and regulation of protective memory T cell responses to Mtb infection, and identifying the mechanisms whereby HIV infection impairs protective T cell immunity to Mtb, will be of vital importance to facilitate development of effective TB vaccines and targeted immunotherapeutic interventions and treatment of individuals co-infected with HIV and Mtb that are necessary to curb the TB epidemic worldwide.
Co-infection with human immunodeficiency virus (HIV) is the single greatest risk factor for reactivation of latent Mycobacterium tuberculosis infection (LTBI) and progression to TB disease. Understanding how co-infection with HIV perturbs innate and adaptive immune control of LTBI is essential for rational design of TB vaccines, and for development of immunotherapeutic approaches to augment protective immunity to M. tuberculosis in persons living with HIV.