Programmed death-1 expression on CD4+ and CD8+ T cells in treated and untreated HIV disease

Abstract

Background There is intense interest in the role of programmed death 1 (PD-1) in causing persistent T-cell dysfunction in HIV infection. However, the impact of HIV infection and antiretroviral treatment (ART) on the expression of PD-1 on T cells is still poorly defined. Methods PD-1 was measured longitudinally in a cohort of recently HIV-infected individuals (n = 121) who started ART early (<6 months after infection) vs. later (≥2 years after infection). PD-1 was also measured cross-sectionally in a diverse cohort of chronically HIV-infected adults (n = 206). Results PD-1 expression levels were high on CD8+ T cells during early HIV infection. PD-1 levels increased on both CD4+ and CD8+ T cells populations in those who delayed therapy (11 and 10%/year, respectively). PD-1 levels declined and were similar in those treated early vs. late after 1 year of ART. In both cohorts, PD-1 expression on CD4+ T cells was associated with CD4+ T-cell activation (CD38+HLA-DR+) and inversely with CD4+ cell count. In contrast, PD-1 expression on CD8+ T cells was most strongly associated with CD8+ T-cell activation and with plasma viral load in viremic individuals. Conclusion Across two large cohorts of untreated and treated individuals, we found consistent associations between HIV RNA levels, CD8+ T-cell activation and PD-1 expression on CD8+ T cells. In contrast, CD4+ T-cell counts and CD4+ T-cell activation were more consistent correlates of PD-1 expression on CD4+ T cells. PD-1 expression appears to be driven by both direct antigen and homeostatic pathways.

Residual inflammation and viral reservoirs

“…Immune checkpoint molecules (ICs) are key players in this arsenal of regulatory factors by modulating the duration and magnitude of immune responses. PD-1, the archetype immune checkpoint, is highly expressed on CD4 + and CD8 + T cells during HIV infection and its expression is not fully normalized by ART [80]. During ART, PD-1 expression is related to CD4 + T cell homeostasis as suggested by its association with CD4 + T cell count [80] and its up regulation by γ-c-cytokines such as IL-7 [81].…”

“…PD-1, the archetype immune checkpoint, is highly expressed on CD4 + and CD8 + T cells during HIV infection and its expression is not fully normalized by ART [80]. During ART, PD-1 expression is related to CD4 + T cell homeostasis as suggested by its association with CD4 + T cell count [80] and its up regulation by γ-c-cytokines such as IL-7 [81]. In addition, the expression of PD-1 on CD4 + T cells is associated with virological markers of HIV persistence suggesting a connection between PD-1 and HIV persistence [6, 7].…”

Immune checkpoint blockade in infectious diseases

“…Many studies have shown a significant correlation between the frequency of PD-1 + CD4 + and CD8 + T cells with HIV persistence on ART in blood 63,65,66 , lymph node 67 and the gastrointestinal tract, which has almost three times the frequency of PD-1 + CD4 + T cells compared to lymph node or blood 68 . However, the most direct evidence of a clear relationship between HIV persistence and PD-1 expression comes from sorting CD4 + T cells from blood where a 10-fold enrichment of HIV in PD-1 high compared to PD-1 low CD4 + T cells was observed 63 .…”

Differential Dynamics of HIV Infection in Humanized MISTRG versus MITRG Mice

“…During acute infection, T EMRA were positive for PD-1 expression, which is a regulator of T cell activation (49) and a marker of exhaustion during viral infections (50,51). The expression of PD-1 in hu mice was reminiscent of the findings in humans suffering from acute HIV infection (44,52). However, at the later stage of infection, an increase in PD-1 levels was also observed on CD4 + T CM and T EM , as well as on CD8 + T EM , resembling the findings in individuals in chronic stages of HIV infection…”