Recognition of the Highly Conserved YMDD Region in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by HLA-A2-Restricted Cytotoxic T Lymphocytes from an Asymptomatic Long-Term Nonprogressor

Abstract

The human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT) is an important target for therapeutic intervention and for HIV-l-specific cytotoxic T lymphocytes (CTL). An HLAA2-restricted CTL epitope containing the sequence YMDD, which is highly conserved among human and animal retroviruses and essential for function of the RNA-dependent DNA polymerase, is identified. The drug resistance mutation at RT amino acid 184 (MI84V), associated with (−)-2′-deoxy-3′-thiacytidine (lamivudine), (−)-2′-deoxy-5-ftuoro-3′-thiacytidine (FTC), and dideoxyinosine resistance, is located within this epitope and abolishes recognition by an established CTL response. This study demonstrates that the CTL response may target functionally relevant regions of the RT protein and suggests drug therapy may select for viral variants with altered susceptibility to established cellular immune responses.