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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-γ and TNF-α production of CXCR5 + CD8 +  T cells were reduced by PD-1 pathway blockade, but the production of IFN-γ and TNF-α 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.

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