Dichotomous Roles of Programmed Cell Death 1 on HIV-Specific CXCR5+ and CXCR5- CD8+ T cells during Chronic HIV Infection

Background: CXCR5(+)CD8(+) T cells have been demonstrated to play an important role in the control of chronic viral replication; however, the relationship between CXCR5(+)CD8(+) T cells, HIV disease progression, and programmed cell death 1 (PD-1) expression profile on CXCR5(+)CD8(+) T cells during HIV infection remain poorly understood. Methods: We enrolled a total of 101 HIV patients, including 62 typical progressors, 26 complete responders (CRs), and 13 immune non-responders (INRs). Flow cytometric analysis, immunohistochemical staining, and relative function (i.e., cytokine secretion and PD-1 blockade) assays were performed to analyze the properties of CXCR5(+)CD8(+) T cells. Results: HIV-specific CXCR5(+)CD8(+) T cells in the peripheral blood and distribution of CXCR5(+)CD8(+) T cells in the lymph node (LN) were negatively correlated with disease progression during chronic HIV infection. PD-1 was highly expressed on CXCR5+CD8+ T cells and positively associated with peripheral CD4(+) T cell counts. Functionally, IFN-gamma and TNF-alpha production of CXCR5(+)CD8(+) T cells were reduced by PD-1 pathway blockade, but the production of IFN-gamma and TNF-alpha from CXCR5(+)CD8(+) T cells increased in response to TCR stimulation. Interestingly, PD-1 expression was constantly retained on CXCR5(+)CD8(+) T cells while significantly decreased on CXCR5(+)CD8(+) T cells after successful antiretroviral treatment in chronic HIV-infected patients. Conclusion: PD-1(+)CXCR5(+)CD8(+) T cells are functional cytotoxic T cells during chronic HIV infection. PD-1(+)CXCR5(+)CD8(+) T cells may represent a novel therapeutic strategy for the disease.