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

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-DRint/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1high, TIGIThigh) 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.

HIV-2 mediated effects on target and bystander cells induce plasma proteome remodeling

“…In parallel with the plasma collection, absolute CD4 + T-cell counts and CD4 + T-cell percentages of lymphocytes were performed using the FACS Presto instrument (BD Biosciences). 26 HIV-1 and HIV-2 pVLs were previously determined. 26 , 32 …”

“…Moreover, we and others have shown that both viremic and aviremic PLWH2 display signs of immune pathology, such as expansion of activated and exhausted CD4 + and CD8 + T-cells, B-cells, natural killer cells (NK-cells), NK T-cells (NKT), monocytes, and dendritic cells (DCs). 23 , 24 , 25 , 26 , 27 , 28 , 29 Interestingly, HIV-2 RNA and Gag protein have been found in peripheral blood mononuclear cells and lymphoid tissue of aviremic PLWH2, indicating ongoing viral replication despite having undetectable plasma viral load. 30 , 31 …”

Hierarchical transcriptional network governing heterogeneous T cell exhaustion and its implications for immune checkpoint blockade

“…Chronic stimulations on tumor-infiltrating Tex cells induce high expression of Eomes, which downregulates CD226 (67,96,97). The Eomes-dependent loss of CD226 limits TCR signaling and antitumor effects (98)(99)(100)(101). Moreover, the loss of CD226 has been found to impair T cell response to PD-1 blockade (102)(103)(104).…”

The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion

“…In chronic infection with HIV-1 and HIV-2, downregulation of CD226 has been observed in the peripheral blood: increased CD226 - PD-1 + antigen-specific CD8 + T cells correlated with increased viral load ( 26 , 27 ). CD226 downregulation also occurs in antigen-specific CD8 + T cells in mice chronically infected with LCMV clone 13, a common model used to evaluate T cell exhaustion.…”