Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects

J Immunol. 2017 Nov 1;199(9):3187-3201. doi: 10.4049/jimmunol.1700851. Epub 2017 Oct 2.

Abstract

Select CMV epitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope-specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in coinfected HLA-DR7+ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared with those from an HIV- HCMV+ HLA-DR7+ cohort or with HLA-DR7-restricted CD4+ T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4+ T cells consisted of effector memory or effector memory-RA+ subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38+ and HLA-DR+ The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-ribosyl Cyclase 1 / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / pathology
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • HIV Infections / immunology*
  • HIV Infections / pathology
  • HIV-1 / immunology*
  • HLA-DR7 Antigen / immunology
  • Humans
  • Immunologic Memory
  • Male
  • Membrane Glycoproteins / immunology
  • Viral Proteins / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • HLA-DR7 Antigen
  • Membrane Glycoproteins
  • Viral Proteins
  • CD38 protein, human
  • ADP-ribosyl Cyclase 1