Cytomegalovirus Modulation of CD8 T Cell Phenotype and Function in People Living with HIV-1

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Abstract Background Both human immunodeficiency virus 1 (HIV-1) and cytomegalovirus (CMV) cause lifelong infections that cannot be cured by antiviral chemotherapy due to persistent viral reservoirs. There is mounting evidence that chronic CMV alters immune responses to various subsequent infections, and that large clonal expansions of CMV-specific CD8 T cells in elderly persons denote immune senescence. We propose that CMV co-infection may contribute to dysregulated HIV-1 control. Methods Longitudinal peripheral blood samples and clinical data were prospectively collected over 18 months from 87 PLWH and 47 individuals without HIV-1 infection. All subjects were males (ages 18-28) receiving anti-retroviral therapy (ART) as treatment or pre-exposure prophylaxis (PrEP). HIV-1 viral titers, HIV-1 antigen/antibody screens, and CMV IgM and IgG ELISAs were monitored throughout the study. Flow cytometry and single-cell RNA sequencing were used to assess total and virus-specific CD8 T cells from 65 and 17 individuals, respectively. Results Subjects were categorized as “normal” or “high” CMV responders based on their frequency of CMV-specific CD8 T cells. Normal responses were observed in 112/126 samples (0-3.5% per pentamer used), and 14/126 had high responses (4.2-18%). Of PLWH, high responders had increased HIV-1 viral loads and decreased CD4/CD8 ratios compared to normal responders. Responder status was associated with changes to both pan-CD8 and HIV-1-specific CD8 T cells. The repertoire of CMV-specific CD8 T cells was more expanded in high responders, but overall T cell receptor diversity was not affected. HIV-specific CD8 T cells from high responders exhibited a heightened cytotoxicity transcriptional profile when compared to CD8 T cells from normal responders. Conclusion In our cohort of young PLWH, a subset of individuals displayed a pronounced expansion of CMV-specific CD8 T cells associated with markers of poor HIV-1 control, as well as changes in activation and transcription within CD8 T cells. This suggests an inappropriately elderly immune tone phenotype during HIV-1-CMV co-infection. Further work is needed to assess impacts to the HIV-1 reservoir, viral control, and non-AIDS-associated morbidity in PLWH on ART.

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