Cytotoxic T lymphocytes and viral evolution in primary HIV-I infection

Efforts to develop immune-based therapies for HIV infection have been imped ed by incomplete definition of the immunological correlates of protection. Despite many precedents demonstrating that CD8(+) cytotoxic T lymphocytes a re key mediators of protective anti-viral immunity in non-human animal mode ls, direct evidence that these effector cells control viral replication in HIV-I infection has remained elusive. The first part of this paper describe s a detailed immunological and genetic study founded on evolutionary consid erations. Following infection with HIV-I, virus variants which escaped reco gnition by autologous cytotoxic T lymphocytes were shown to possess a selec tion advantage within the host environment. Cytotoxic T lymphocytes therefo re exert anti-viral pressure in vivo. This observation provides compelling evidence that cytotoxic T lymphocytes comprise a significant element of ant iretroviral immunity. Subsequently, the quantification of peripheral cytoto xic T lymphocyte frequencies utilizing peptide-(human leucocyte antigen cla ss I) tetrameric complexes is described. Five patients with qualitatively s imilar immunodominant cytotoxic T lymphocyte responses during symptomatic p rimary HIV-I infection were stud led longitudinally. Expansions of virus-sp ecific CD8(+) lymphocytes comprising up to 2% of the total CD8(+) T cell po pulation were observed in the acute phase of infection. Antigenic load was identified as an important determinant of circulating HIV-I-specific CD8(+) lymphocyte levels; however, significant numbers of such cells were also fo und to persist following prolonged therapeutic suppression of plasma viraem ia. In addition, an analysis of antigenic sequence variation with time in t his case series suggests that the early administration of combination anti- retroviral therapy may limit HIV-I mutational escape from host cytolytic sp ecificities. The implications of these preliminary data are discussed. The data presented suggest that vaccination protocols should aim to elicit vigo rous cytotoxic T lymphocyte responses to HIV-I. Attempts to stimulate polyv alent responses to mutationally intolerant epitopes are likely to be most e ffective. Optimal management of HIV-I infection requires an understanding o f dynamic host-virus interactions, and may involve strategies designed to e nhance cytotoxic T lymphocyte activity following periods of antiretroviral drug therapy.