Functional and genetic integrity of the CD8 T-cell repertoire in advanced HIV infection.

Abstract

HIV-specific cytotoxic T lymphocytes (CTL) can restrict HIV replication in acute and chronic infection, but disease progression occurs in parallel with declining CTL activity. An understanding of why CTL fail to control HIV replication might reveal important mechanisms of disease progression and enhance prospects for developing effective CTL-based immunotherapies. To investigate the functional integrity, T-cell repertoire diversity, and HIV reactivity of CD8 T lymphocytes in individuals with advanced HIV infection. Individuals were considered to have progressed to advanced HIV infection if their total T-cell count was < 500 x 10(6) cells/(l) on at least two successive clinic visits. CD8 T cells from these individuals were analyzed for CTL function, HIV reactivity and T-cell receptor (TCR) diversity by chromium release assays and reverse transcriptase polymerase chain reaction. CD8 T cells from all individuals with advanced HIV infection proliferated and differentiated into functional CTL in vitro. Despite extremely low T-cell counts and previous AIDS-defining illnesses, six individuals had inducible anti-HIV CTL responses. In two additional cases, HIV-specific CTL activity became detectable following significant treatment-associated remission of T-cell lymphopenia. Assessment of TCRbetaV gene family representation and betaV gene intrafamily diversity indicated CD8 T-cell repertoire diversity is maintained through advanced HIV infection. These data suggest that HIV-specific CTL activity can be selectively compromised while the functional and genetic integrity of the CD8 population as a whole remains intact. A substantial fraction of individuals retain inducible anti-HIV CTL activity through advanced HIV infection and, in at least some cases, effective treatment can restore HIV-specific CTL responses even at this late stage of disease.