Altered ex vivo balance between CD28⁺ and CD28^- cells within HIV-specific CD8⁺ T cells of HIV-seropositive patients

The CD8⁺ CD28^- cell population in the blood of HIV-infected individuals is considerably expanded. Yet the cause of this expansion is not clear. The recent demonstration of identical TCR-rearranged genes in CD8⁺ CD28⁺ and CD8⁺ CD28^- expanded T cells of HIV-seropositive patients supports the hypothesis that these two subpopulations are phenotypic variants of the same lineage. To further elucidate the precise relationship between them, we measured the fraction of CD28⁺ and CD28^- T cell subsets in IFN-γ-producing CD8⁺ T cells by intracellular staining and cytofluorometry as a functional test for ex vivo recognition of epitopes derived from HIV-1, Epstein-Barr virus (EBV) and influenza virus. HIV-specific CD8⁺ T cells were predominantly CD28^- in all the eight HIV-seropositive subjects tested. In contrast, the anti-EBV and anti-influenza CD8⁺ T cells were mainly CD28⁺ in these patients as well as in HIV-seronegative individuals. This supports the notion that the CD8⁺ CD28^- hyperlymphocytosis observed in HIV infection is due mainly to chronic activation and differentiation of HIV-specific memory CD8⁺ CD28⁺ T cells into terminally differentiated CD8⁺ CD28^- lymphocytes, because of intense HIV-1 replication and without any important bystander activation. This clarification of the mechanisms underlying the CD8⁺ CD28^- expansion in HIV-induced pathogenesis may have important therapeutic implications.