CD73 + CD127 high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection

Int J Mol Sci. 2021 Jan 18;22(2):912. doi: 10.3390/ijms22020912.


HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5-10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6-6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1-3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.

Keywords: CD4+ subsets; CD73; HIV-1 viral reservoir.

MeSH terms

  • 5'-Nucleotidase / genetics
  • 5'-Nucleotidase / immunology
  • Antigens, CD / genetics
  • Antigens, CD / immunology*
  • Antigens, CD / therapeutic use
  • Cell Lineage / genetics
  • Cell Lineage / immunology
  • Cell Proliferation / genetics*
  • HIV Infections / genetics*
  • HIV Infections / immunology
  • HIV Infections / pathology
  • HIV Infections / virology
  • HIV-1 / immunology
  • HIV-1 / pathogenicity
  • Humans
  • Interleukin-7 Receptor alpha Subunit / genetics
  • Interleukin-7 Receptor alpha Subunit / immunology
  • Memory, Long-Term / physiology
  • Molecular Targeted Therapy*


  • Antigens, CD
  • Interleukin-7 Receptor alpha Subunit
  • 5'-Nucleotidase