CHARACTERIZING THE EFFECTS OF HIV, M.TB, AND HIV/M.TB CO-INFECTIONS ON LUNG CD4+ T CELL SUBSETS USING HUMANIZED MICE

Abstract

The Human Immunodeficiency Virus (HIV) compromises the immune system by depleting mainly CD4+ T cells, which can be categorized into subsets based on their differentiation states and functions. HIV disrupts the intricate balance between these subsets. This is suggested to cause people living with HIV (PLWH) heightened susceptibility to opportunistic infections by pathogens such as Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB) and leading cause of death among PLWH. Little is known about the immune responses during co-infection in specifically the lungs, despite the lungs being a crucial site where HIV and M.tb first interact. This project aimed to address this research gap by characterizing effects of HIV-1 on the different lung CD4+ T cell subsets during co-infection. We observed a significant depletion of the lung CD4+ effector (TEFF) and effector memory (TEM) cells during HIV infection, but opposite trends towards increase were seen for these two subsets in the lungs during M.tb infection. Interestingly, although the HIV/M.tb co-infected mice had significantly reduced CD4+ T cell absolute counts in the lungs compared to Mtb-infected mice, their subset compositions were similar. We hypothesized that M.tb-induced stimulation could cause an influx of TEM and TEFF cells that were important to TB defense, inadvertently counterbalancing their depletion by HIV and seemingly maintaining their relative frequencies despite the progressive loss in their actual numbers. We have also examined HIV’s impact on the CD4+ T cells’ functionality: while HIV skewed the Th1 cells’ cytokine profile to become more monofunctional, M.tb infection promoted an expansion of the polyfunctional Th1 subset. In co-infected lungs, the Th1 cells’ cytokine profile remained disrupted, suggesting that HIV might exert irreversible damage on the lung CD4+ T cells’ functionality. Further investigation will be needed to validate these hypotheses and better understand the interplay between HIV and TB.