CMV epitope-specific CD4+ T cells are inflated in HIV+ CMV+ subjects

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 tetramers loaded with the glycoprotein-B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in co-infected, HLA-DR7+ long-term non-progressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared to those from a HIV− HCMV+ HLA-DR7+ cohort, or to HLA-DR7-restricted CD4+ T cells from the HIV co-infected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, Epstein-Barr virus nuclear antigen 2 or HIV gag protein. Inflated DYS-specific CD4+ T cells comprised effector memory or effector memory-RA+ subsets with restricted TCR-beta 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 were less often CD38+HLA-DR+ co-expressing. 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.