Specific recognition of lamivudine-resistant HIV-1 by cytotoxic T lymphocytes

Objective: The reverse transcriptase (RT) M184V mutation within the HLA-A2-restricted HIV-1 cytotoxic T lymphocyte (CTL) epitope VL9 (VIYQYMDDL; RT 179-187) not only induces drug escape against lamivudine but also abolished recognition by a CTL clone derived from a long-term non-progressor. To test whether the variant VL9 epitope containing the M184V mutation represents a new CTL epitope, we studied recognition of this epitope in a cohort of HLA-A2-positive HIV-1-infected patients. Methods: Peripheral blood mononuclear cells isolated from 28 HIV-1-infected patients were stimulated with the peptide VIYQYVDDL, containing the M184V mutation. Outgrowing cell lines were tested for specific recognition in a standard chromium-release assay. Results: In one subject, a CTL line could be isolated recognizing the peptide VIYQYVDDL in conjunction with HLA-A2. The CTL clone also recognized the M1841 mutation, but it failed to recognize the wild-type epitope VIYQYMDDL. Conclusion: CTL can specifically recognize lamivudine-resistant HIV-1 variants. Therefore, the cellular immune response could have an important influence on the control of drug-resistant virus. Furthermore, this demonstrates that the immune system can generate new CTL specificities even in patients with advanced disease, as the M184V HIV variants emerges only after drug treatment. Specific immunotherapy against this epitope might be helpful in delaying or preventing lamivudine resistance. (C) 2000 Lippincott Williams & Wilkins.