De Novo Generation of Escape Variant-Specific CD8 + T-Cell Responses following Cytotoxic T-Lymphocyte Escape in Chronic Human Immunodeficiency Virus Type 1 Infection

作者：Todd M. Allen, Xu G. Yu, Elizabeth T. Kalife, Laura L. Reyor, Mathias Lichterfeld, Mina John, Michael L. Cheng, Rachel L. Allgaier, Stanley K. Mui, Nicole Frahm, Galit Alter, Nancy V. Brown, Mary N. Johnston, Eric Rosenberg, S. Mallal, Christian Brander, Bruce D. Walker, Marcus Altfeld · 发表于：Journal of Virology · 年份：2005 · DOI：10.1128/jvi.79.20.12952-12960.2005 · 被引用次数：136 · 研究领域：HIV Research and Treatment、Immune Cell Function and Interaction、Cytomegalovirus and herpesvirus research

Human immunodeficiency virus type 1 (HIV-1) evades CD8(+) T-cell responses through mutations within targeted epitopes, but little is known regarding its ability to generate de novo CD8(+) T-cell responses to such mutants. Here we examined gamma interferon-positive, HIV-1-specific CD8(+) T-cell responses and autologous viral sequences in an HIV-1-infected individual for more than 6 years following acute infection. Fourteen optimal HIV-1 T-cell epitopes were targeted by CD8(+) T cells, four of which underwent mutation associated with dramatic loss of the original CD8(+) response. However, following the G(357)S escape in the HLA-A11-restricted Gag(349-359) epitope and the decline of wild-type-specific CD8(+) T-cell responses, a novel CD8(+) T-cell response equal in magnitude to the original response was generated against the variant epitope. CD8(+) T cells targeting the variant epitope did not exhibit cross-reactivity against the wild-type epitope but rather utilized a distinct T-cell receptor Vbeta repertoire. Additional studies of chronically HIV-1-infected individuals expressing HLA-A11 demonstrated that the majority of the subjects targeted the G(357)S escape variant of the Gag(349-359) epitope, while the wild-type consensus sequence was significantly less frequently recognized. These data demonstrate that de novo responses against escape variants of CD8(+) T-cell epitopes can be generated in chronic HIV-1 infection and provide the rationale for developing vaccines to induce...