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Background:  Cytotoxic T lymphocytes (CTL) are thought to play a critical role in controlling HIV replication during infection. HLA B57 and the closely related HLA B5801 are strongly associated with long-term nonprogressive HIV-1 infection. Although the HLA B57/B5801-restricted CTL responses have been studied extensively, the mechanism behind the mediated protection remains unclear. Recently described mutations in the HLA-B57/5801 epitope TSTLQEQIGW (T242N and G248X) were associated with viral escape and loss of viral fitness. In our present study, we tested whether the HLA B57/5801-restricted CTL responses enforce a strong selective pressure on HIV-1, resulting in viral escape mutants with reduced viral fitness.

Methods:  Biological virus clones were isolated from cryo-preserved peripheral blood mononuclear cell samples that were obtained longitudinally in the course of infection of 5 HLA B57/5801 individuals, 2 of which showed typical progression and 3 of which showed slow progression. To study viral evolution, regions of the gag gene, including the TSTLQEQIGW epitope, were sequenced and analyzed.

Results:  The mutations T242N and G248X in TSTLQEQIGW that are associated with CTL escape were present in all longitudinally obtained HIV-1 clones from all 5 individuals, irrespective of the clinical course of their infections. We are currently analyzing whether typical and slow progressors have different dN/dS ratios in their HIV gag genes.

Conclusions:  In this study we show that viral evolution associated with an HLA B57/5801-directed immune response is present in both typical progressors and slow progressors. Because the escape mutations are observed in both normal and slow progressors, the clinical relevance of these mutations is unproven.

Keywords: HLA B57/5801; CTL; escape