Increased frequency of cytotoxic CXCR5+effector memory CD8+T cells during natural control of HIV-1 infection

Abstract

Purpose: Potent HIV-specific immune responses and a small latent viralreservoir are likely required to control viral replication during HIV-1 infection.Here we investigated the antiviral CD8 + T cell response of elite and viremic controllers (EC and VC) and antiretroviral therapy-(ART) suppressed patients atbaseline and after peptide stimulation.Method: Peripheral blood mononuclear cells of 58 patients were analyzed by18 color flow cytometry and IFN-c ELIspot at baseline and after 7 days ofin vitro HIV peptide stimulation (PTE GAG pool, NIH). Plasmas were analyzedfor IFN-c, CXCL-10, IL1-b, IL6, TNF-a, IL-18 concentrations. Cytometry datawas clustered using viSNE and analyzed by Boolean gating strategy to assessmultifunctional characteristics. Statistical comparison was executed withQluCore and Prism nonparametric statistics (Kruskal-Wallis test correcting formultiple comparison).Results: IL-18 in plasma and CD38 expression on CD4 + T cells weresignificantly lower in EC and ART patients with low reservoir than in VC(p<0.05). We observed a significant increase in IFN-y production at baselineand after 7 days of peptide stimulation (p<0.0005) while CD107a and Ki67expression were also significantly increased for ECs compared to ART patients(p<0.001).Detailed phenotyping revealed that CD8 + effector memory T cells which areIFN-c+, Ki67+, CD107abright, Perforinbrightand GrzB+significantly increased inEC (p<0.005) as compared to VC and ART patients. Similarly we observedcentral memory CD8 + T cells subsets with increased cytotoxic andpolyfunctional features in EC (p<0.005). Interestingly, CD8 + T cells subsetsexpressing CXCR5, a homing receptor for lymph node follicles, and cytotoxicmarkers were significantly increased in EC as well (p<0.005).Conclusion: Distinct functional subsets coexist during natural control of HIV-1 infection. Access to the B cell zone of lymph node follicles by cytotoxicCD8 + T cells might explain long-term control of the HIV reservoir.