Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals

Lydia Scharf; Christina B Pedersen; Emil Johansson; Jacob Lindman; Lars R Olsen; Marcus Buggert; Sten Wilhelmson; Fredrik Månsson; Joakim Esbjörnsson; Antonio Biague; Patrik Medstrand; Hans Norrgren; Annika C Karlsson; Marianne Jansson; SWEGUB CORE Group

doi:10.3389/fimmu.2021.744530

Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals

Front Immunol. 2021 Oct 12:12:744530. doi: 10.3389/fimmu.2021.744530. eCollection 2021.

Authors

Affiliations

¹ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
² Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.
³ Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
⁴ Department of Laboratory Medicine, Lund University, Lund, Sweden.
⁵ Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
⁶ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Translational Medicine, Lund University, Lund, Sweden.
⁸ National Laboratory for Public Health, Bissau, Guinea-Bissau.

Abstract

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DR^int/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1^high, TIGIT^high) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.

Keywords: CD226; CD8 T cell phenotypes; HIV-2; T cell exhaustion; TIGIT; aviremic; costimulation; immune activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
CD8-Positive T-Lymphocytes / immunology*
Female
HIV Infections / immunology*
HIV Infections / virology*
HIV Seronegativity / immunology
HIV-2 / immunology*
Humans
Immunosenescence / immunology*
Male
Middle Aged
Viremia / immunology