The effect of HIV infection on CD4 T cell immunity to Mycobacterium tuberculosis

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Project Summary / Abstract Infection with Mycobacterium tuberculosis (Mtb) results in 10 million cases of active tuberculosis (TB) disease each year and is the leading cause of death due to a single infectious agent. Although the correlates of protective immunity to Mtb are not clearly defined, co-infection with human immunodeficiency virus (HIV) is a significant risk factor for development of active TB disease. Moreover, the increased risk of TB disease is evident within the first year of HIV seroconversion, suggesting that impairment of immunity to Mtb occurs early after HIV infection. Although there is compelling evidence that HIV infection is associated with CD4 T cell dysfunction, the molecular mechanisms by which HIV infection impairs CD4 T cell responses to Mtb are unknown. The focus of this proposal is to determine the effect of HIV infection and treatment on the phenotype, function, epigenome and transcriptome of CD4 T cell responses to Mtb. We will leverage blood samples collected from a unique, well- characterized longitudinal cohort of women at high-risk for HIV infection in Mombasa, Kenya to test the hypotheses that (i) HIV infection modifies the epigenome and transcriptome of CD4 T cells to promote differentiation of dysfunctional CD4 T cells; and (ii) early initiation of antiretroviral therapy (ART), prior to HIV- induced CD4 T cell deficiency, preserves the molecular program and functional capacity of CD4 T cell responses that may contribute to enhanced immune control of Mtb. We will use longitudinal samples to conduct high- dimensional flow cytometry to define the phenotype and function of total and Mtb-specific CD4 T cells before and after HIV infection, and before and after ART. At each time point, we will also define the chromatin accessibility landscape, DNA methylome, and transcriptome of the total CD4 T cell population. Lastly, we will use cutting edge, single-cell RNA-sequencing to determine the effect of HIV infection and treatment on the transcriptional state of Mtb-specific CD4 T cells. These studies will generate unprecedented, novel insights into the phenotypic, functional, transcriptomic, and epigenetic profiles of CD4 T cells in HIV infection. Moreover, our genome-wide studies will define the molecular program of CD4 T cells in HIV infection and will potentially identify novel genes, pathways, and transcription factor-based regulatory modules that can be leveraged to enhance durable CD4 T cell-mediated control of Mtb.