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164
Immune Control and Immune Failure in HIV Infection
B D Walker, T Allen, M Altfeld, X Yu, P Goulder, M Addo, R Dranert, C Brander, N Frahm, M Johnston, C Corcoran, H Trong, P Lee, E Maier, K O’Sullivan, R Eldridge, M Johnston, E Rosenberg, C Hess, A Luster
Partners AIDS Res Ctr, Massachusetts Gen Hosp and Harvard Med Sch, Boston MA
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Background: Increasing evidence suggests that cellular immune responses play a pivotal role in the long-term control of HIV replication in vivo. However, the persistence of immune control and the factors leading to loss of immune control remain unclear.
Methods: Studies of cellular immune function were performed in cohorts of persons with different disease outcomes. These included persons with progressive uncontrolled infection despite antiviral therapy, persons with persistent control in the ence of therapy, and persons treated in acute infection. Longitudinal immunologic follow-up was performed in persons subjected to an STI protocol which required re-treatment if viral load remained above 5,000 copies for greater than 3 weeks, or was in excess of 50,000 copies on any single occasion.
Results: Lack of persistent control of viremia was observed despite strong virus-specific CD8 T-cell responses to HIV in all groups. In persons with treated acute infection followed by treatment interruption, multiple cases of late breakthrough following prolonged immune containment were observed, some after more than 600 days off therapy. Investigations of the causes of loss of immune control have revealed one case of documented superinfection, whereas others appear to be associated with gradual genetic evolution of the initial virus. Phenotypic studies have revealed complete maturation of cells in persons who control viremia. However, the presence of strong CTL responses and lack of escape has been observed in some persons with chronic uncontrolled infection.
Conclusions: These data indicate that despite initial control of viremia, durable immune control in persons following treated acute infection is more difficult to achieve, and that larger trials will be needed to determine the potential clinical and virologic benefit of this approach. Moreover, detailed studies in persons with progressive HIV infection show that in some cases strong CTL responses persist into the later stages of illness in the ence of immune escape. These data are relevant to current efforts to develop an AIDS vaccine designed to retard disease progression rather than prevent infection, and indicate that durable maintenance of low level viremia may be difficult to achieve.
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