Transcriptional analysis of human peripheral CXCR5mem and CXCR5neg HIV-specific CD4 T cells in progressive disease

The virus-specific CD4+ T cell dysfunction associated with failure to control chronic infections is poorly understood in humans. A striking enrichment of a Tfh signature is observed in ex vivo stimulated HIV-specific CD4 T cells of Chronic progressors (CPs) compared to Elite controls (ECs), which was not due to a higher fraction of CXCR5mem HIV-specific CD4 in CPs. Here, we sought to define the cell subsets that contributed to the TFH transcriptional signature observed in CPs, applying microarray analysis to paired live-sorted subsets of CXCR5mem and CXCR5neg HIV-specific CD4+ T cells from CPs and ECs . The Tfh signature was not confined to TFH but also atypically enriched in CXCR5neg non-TFH cells and increased expression of key TFh molecules were enriched in the CXCR5neg HIV-specific CD4 T cells of CPs compared to ECs. Thus, altered differentiation is central to HIV-specific CD4+ T cell impairment and involves both gain and loss of functions. CXCR5mem and CXCR5neg HIV-specific CD4 T cells were live-sorted after a 9-h stimulation of PBMCs with an HIV Gag peptide pool. HIV-specific CD4 T cells were identified based on coupregulation of activation markers CD40L and CD69. The HIV-infected individuals were categorized in 2 groups: “Chronic progressors (CP) (n=5), defined as people with a viral load of more than 5,000 vRNA copies per ml of plasma; ; and elite controllers (EC) (n=4), defined as subjects who spontaneously controlled viremia to below 50 RNA copies per ml plasma in the absence of therapy.