HIV-1 infection and the lack of viral control are associated with greater expression of interleukin-21 receptor on CD8+ T cells

AIDS. 2021 Jul 1;35(8):1167-1177. doi: 10.1097/QAD.0000000000002864.


Objectives: Interleukin-21 (IL-21) has been linked with the generation of virus-specific memory CD8+ T cells following acute infection with HIV-1 and reduced exhaustion of CD8+ T cells. IL-21 has also been implicated in the promotion of CD8+ T-cell effector functions during viral infection. Little is known about the expression of interleukin-21 receptor (IL-21R) during HIV-1 infection or its role in HIV-1-specific CD8+ T-cell maintenance and subsequent viral control.

Methods: We compared levels of IL-21R expression on total and memory subsets of CD8+ T cells from HIV-1-negative and HIV-1-positive donors. We also measured IL-21R on antigen-specific CD8+ T cells in volunteers who were positive for HIV-1 and had cytomegalovirus-responding T cells. Finally, we quantified plasma IL-21 in treatment-naive HIV-1-positive individuals and compared this with IL-21R expression.

Results: IL-21R expression was significantly higher on CD8+ T cells (P = 0.0256), and on central memory (P = 0.0055) and effector memory (P = 0.0487) CD8+ T-cell subsets from HIV-1-positive individuals relative to HIV-1-negative individuals. For those infected with HIV-1, the levels of IL-21R expression on HIV-1-specific CD8+ T cells correlated significantly with visit viral load (r = 0.6667, P = 0.0152, n = 13) and inversely correlated with plasma IL-21 (r = -0.6273, P = 0.0440, n = 11). Lastly, CD8+ T cells from individuals with lower set point viral load who demonstrated better viral control had the lowest levels of IL-21R expression and highest levels of plasma IL-21.

Conclusion: Our data demonstrates significant associations between IL-21R expression on peripheral CD8+ T cells and viral load, as well as disease trajectory. This suggests that the IL-21 receptor could be a novel marker of CD8+ T-cell dysfunction during HIV-1 infection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • CD8-Positive T-Lymphocytes
  • HIV Infections*
  • HIV-1*
  • Humans
  • Interleukin-21 Receptor alpha Subunit
  • Receptors, Interleukin-21
  • Viral Load


  • IL21R protein, human
  • Interleukin-21 Receptor alpha Subunit
  • Receptors, Interleukin-21