Differential characteristics of cytotoxic T lymphocytes restricted by the protective HLA alleles B∗27 and B∗57 in HIV-1 infection

Abstract

Objective: HLA-B∗27 and B∗57 are associated with relatively slow progression to AIDS. Mechanisms held responsible for this protective effect include the immunodominance and high magnitude, breadth, and affinity of the cytotoxic T lymphocytes (CTL) response restricted by these HLA molecules, as well as superior maintenance of CTL responses during HIV-1 disease progression. Design: We examined CTL responses from HIV-1-infected individuals restricted through protective and nonprotective HLA alleles within the same host, thereby excluding any effects of slow or rapid progression on the CTL response. Results: We found that neither immunodominance, nor high magnitude and breadth, nor affinity of the CTL response are general mechanisms of protection against disease progression. HLA-B∗57-restricted CTL responses were of exceptionally high affinity and dominated the HLA-A∗02-restricted CTL response in individuals coexpressing these HLA alleles. In contrast, HLA-B∗27-restricted CTL responses were not of particularly high affinity and did not dominate the response in individuals coexpressing HLA-B∗27 and HLA-A∗02. Instead, in individuals expressing HLA-B∗27, the CTL response restricted by nonprotective HLA alleles was significantly higher and broader, and of higher affinity than in individuals expressing these alleles without HLA-B∗27. Although HLA-B∗27 and B∗57 are thought to target the most conserved parts of HIV, during disease progression, CTL responses restricted by HLA-B∗27 and B∗57 were lost at least as fast as CTL responses restricted by HLA-A∗02. Conclusions: Our data show that many of the mechanisms of CTL that are generally held responsible for slowing down HIV-1 disease progression hold for HLA-B∗57 but do not hold for HLA-B∗27.