(O4) Activated and exhausted CD8 T-cells differentiate aviremic HIV-2 infected from seronegative individuals

Författare/Medförfattare

Lydia Scharf1, Christina B Pedersen2, Jakob Lopakto Lindman3, Lars R Olsen2, Sten Wilhelmson4, Fredrik Månsson4, Joakim Esbjörnsson4, Antonio Biague6, Patrik Medstrand4, Hans Norrgren3, Marianne Jansson5*, Annika C Karlsson1* and the SWEGUB GORE Group7

Affiliates

1: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden, 2: Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark, 3: Department of Clinical Sciences Lund, 4: Department of Translational Medicine, 5: Department of Laboratory Medicine, Lund University, Lund, Sweden, 6: National Laboratory for Public Health, Bissau, Guinea-Bissau, 7: The Swedish Guinea-Bissau Cohort Research Group* Equal contributions

Abstrakt

Background
HIV-2 is in general associated with reduced pathogenicity compared to HIV-1. This phenomenon greatly stems from a larger proportion of individuals that better control the virus naturally. Due to the importance of CD8 T-cell responses in the control of HIV, detailed characterization of the immunophenotype of these cells in HIV-2 infection might guide development of HIV therapies.

Methods
To investigate activation and exhaustion of CD8 T-cells, we collected peripheral blood samples from a cohort in Guinea-Bissau, including HIV-seronegative, aviremic and viremic HIV-2-infected individuals. The immunophenotype of CD8 T-cell populations was analyzed using multicolor flow cytometry, FlowJo, PRISM and R software. In addition to manual gating, computational clustering was performed.

Results
Unbiased automated gating analysis of CD8 T-cells identified clusters of activated and exhausted cell populations significantly differentiating the study groups. Guided by the identified clusters, we analyzed manually gated populations expressing markers of activation (CD38 and HLA-DR) and immune exhaustion (programmed death-1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and 2B4). The analysis revealed higher frequencies of CD8 T-cells co-expressing both immune activation markers, CD38 and HLA-DR, together with any of the immune exhaustion markers TIGIT, 2B4 or PD-1 in the aviremic HIV-2-infected group compared to seronegatives. These cell populations, in additional to others, defined by the expression of single activation or exhaustion markers, were found to be significantly differently between the aviremic and viremic HIV-2 groups. Both processes, activation and exhaustion, were closely linked to one another and increased with HIV-2-induced immunodeficiency.

Conclusions
While our results suggest that aviremic HIV-2-infected individuals show few signs of pathological changes regarding their immunophenotype, we still identified specific activated and exhausted CD8 T-cell populations that circulate also in individuals with low or no HIV-2 viremia. More detailed knowledge of these mechanisms can serve both as biomarkers for therapy monitoring and direct targets for immunotherapy.