CD4(+) T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection

HIV type 2 (HIV-2) represents an attenuated form of HIV, in which many infected individuals remain ‘aviremic’ without antiretroviral therapy. However, aviremic HIV-2 disease progression exists, and in the current study, we therefore aimed to examine if specific pathological characteristics of CD4(+) T cells are linked to such outcome. DESIGN: HIV-seronegative (n = 25), HIV type 1 (HIV-1) (n = 33), HIV-2 (n = 39, of whom 26 were aviremic), and HIV-1/2 dually (HIV-D) (n = 13)-infected study participants were enrolled from an occupational cohort in Guinea-Bissau. METHODS: CD4(+) T-cell differentiation, activation, exhaustion, senescence, and transcription factors were assessed by polychromatic flow cytometry. Multidimensional clustering bioinformatic tools were used to identify CD4(+) T-cell subpopulations linked to infection type and disease stage. RESULTS: HIV-2-infected individuals had early and late-differentiated CD4(+) T-cell clusters with lower activation (CD38(+)HLA-DR(+)) and exhaustion programmed death-1 (PD-1) than HIV-1 and HIV-D-infected individuals. We also noted that aviremic HIV-2-infected individuals possessed fewer individuals. CD4(+) T cells with pathological signs compared to other HIV-infected groups. Still, compared to HIV-seronegative individuals, aviremic HIV-2-infected individuals had T-bet(+) CD4(+) T cells that showed elevated immune activation/exhaustion, and particularly the frequencies of PD-1(+) cells were associated with a suboptimal percentage of CD4(+) T cells. CONCLUSION: Increased frequencies of CD4(+) T cells with an activated/exhausted phenotype correlate with exacerbated immunodeficiency in aviremic HIV-2-infected individuals. Thus, these findings encourage studies on the introduction of antiretroviral therapy also to individuals with aviremic HIV-2 infection.