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

Abstract

Both human immunodeficiency virus 1 (HIV-1) and cytomegalovirus (CMV) cause lifelong infections that cannot be cured by antiviral chemotherapy due to persistent latent viral reservoirs. CMV frequently co-infects people living with HIV-1 (PLWH). 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 are markers of immune senescence. We propose that CMV co-infection may contribute to dysregulated viral control in PLWH. 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. T cell surface protein expression and HIV-1 and CMV-specific pentamer staining were assessed using flow cytometry on longitudinal samples from 65 individuals. Viral-specific CD8 T cells isolated from 17 PLWH using barcoded antigen dextramer staining were profiled by gene expression and T cell receptor repertoire sequencing using single-cell RNA sequencing. Individuals were categorized as “normal” or “high” CMV responders based on their frequency of CMV-specific CD8 T cells. Of 126 specimens evaluated via flow cytometry, 112 had normal CMV-specific CD8 T cell responses (0-3.5% of CD8 T cells per pentamer used), and 14 had high responses (4.2-18%). All high responders (6/65, 9.2%) had chronic HIV-1 infection, their HIV-1 viral loads were increased, and CD4/CD8 T cell ratios were decreased compared to PLWH with normal CMV responses. CMV responder status was associated with changes in the size and phenotypes of both pan-CD8 and HIV-1-specific CD8 T cells. High responders’ expansions of CMV-specific CD8 T cells appeared largely clonal without affecting overall diversity of the CMV response. HIV-specific CD8 T cells from a high responder exhibited a heightened cytotoxicity transcriptional profile when compared to those from a normal responder. In our cohort of young PLWH, we observed a subset of CMV-positive individuals with a marked expansion of CMV-specific CD8 T cells associated with markers of poor HIV-1 control, as well as changes in activation and transcriptional profiles of both total and HIV-1-specific CD8 T cells. This suggests an inappropriately elderly immune tone phenotype with 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.