COEVOLUTION OF HUMAN-IMMUNODEFICIENCY-VIRUS AND CYTOTOXIC T-LYMPHOCYTE RESPONSES

After more than a decade of intensive research, the precise role of hu man immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL ) in determining the course of the infection remains open to argument. It is established that HIV-specific CTL appear early in the infection and are temporally associated with the clearance of culturable virus from the blood; that CLL are generally detectable at very high levels throughout the asymptomatic phase and decline at the time of progressi on to AIDS; and that CTL-mediated killing is sufficiently fast to prev ent production of new virions by HIV-infected cells. However, viral tu rnover is high throughout the course of the infection, and infected in dividuals progress inexorably to disease in spite of the CTL response. In order to address the question of whether CTL play an active part i n influencing the course of HIV infection, one approach has been to se ek evidence for CTL-mediated selection pressure on the virus. Several clear examples of CTL epitope-specific mutations selected to fixation are described. We argue that CTL escape is a common event which occurs at all stages of the infection. Detailed longitudinal studies are req uired to detect CTL escape and to understand the complexities contribu ted by factors such as a polyvalent CTL response and the presence of e pitope variants which antagonise the CTL response. In conclusion, ther e is strong evidence of a dynamic process in which CTL impose importan t selection constraints upon HIV from which the virus attempts to esca pe; ultimately, at the time of disease progression, the tenuous contro l of CTL over the virus is lost.