Martinez-Martinez, Y. B.; Huante, M. B.; Naqvi, K. F.; Shah, M. N.; Lisinicchia, J. G.; Files, M. A.; Perez, J.; Gelman, B. B.; Endsley, M. A.; Endsley, J. J.

Tuberculosis (TB) kills an estimated 1.25 million people annually and is the leading cause of death in people with HIV (PWH) (1). The CD4+ T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb) and are essential hosts for HIV pathogenesis. Emerging evidence in blood and gastrointestinal mucosa of PWH suggests that, among Th cells, Th17 and Th22 may be preferentially depleted during HIV infection. Targeting of Th17 and Th22 cells by HIV could pose important and poorly understood risks for Mtb containment in those with co-infection. Mtb-driven activation of Th17 and Th22 immunity may also contribute to HIV proliferation and persistence. We employed a humanized mouse model of co-infection to assess changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. In infected mice, Th17 cells were the predominant host for HIV in spleen and shown to be a source of HIV replication in pulmonary TB granulomas. Th17 cells were increased in lung of mice with TB or TB-HIV. Conversely, Th22 cells were reduced in mice with HIV or TB-HIV. Mtb infection increased the viral load in lung of co-infected mice while HIV suppressed the pulmonary Th17 family cytokine response to Mtb including IL-6, IL-22, IL-23, and IL-1{beta}. Differential transcriptome assessment demonstrated that HIV co-infection disrupted Th17 pathways activated by Mtb in lung. Overall, these results suggest that HIV may compromise Th22 immunity and exploit Th17 cells to promote viral pathogenesis in the setting of Mtb and HIV co-infection.