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.

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