BACKGROUND: HIV-1 protease is subjected to dual selection pressure exerted by protease inhibitors (PIs) and cytotoxic T lymphocytes (CTL). Recently, we identified KMIGGIGGF (KF9) as a HLA-B*1501-restricted CTL epitope, including several major PI resistance mutations (M46I/L, I47A/V, G48V, I50V). To assess potential interactions between KF9-specific CTL and emergence of these important resistance mutations, we studied CTL recognition of the mutations and analyzed protease sequences in an HLA-I–typed patient cohort. METHODS: CTL recognition of KF9 and resistance mutations in KF9 were studied in 38 HLA-B*1501-positive HIV-1–infected patients using variant KF9 peptides in interferon-g enzyme-linked immunospot assays. Protease sequences were analyzed in 302 HLA-I–typed HIV-1–infected patients. RESULTS: G48V abolished KF9 recognition by CTL in all patients. Furthermore, M46I, I47A, and I50V could impair or abolish CTL recognition in many patients. In contrast, M46L and I47V showed good CTL recognition in nearly all patients. HIV-1 protease sequence analysis showed no statistical correlation between the occurrence of resistance mutations in KF9 and HLA-B*1501. Viral load in patients failing therapy with KF9 mutations was significantly lower in HLA-B*1501-positive patients in comparison with HLA-B*1501-negative patients. CONCLUSIONS: PI mutations, G48V, M46I, and I47A, can abrogate CTL recognition, indicating potential interactions between development of drug resistance and CTL response. However, we could not find evidence that development of these PI mutations is influenced by KF9-specific CTL.
BACKGROUND:HIV-1 protease is subjected to dual selection pressure exerted by protease inhibitors (PIs) and cytotoxic T lymphocytes (CTL). Recently, we identified KMIGGIGGF (KF9) as a HLA-B*1501-restricted CTL epitope, including several major PI resistance mutations (M46I/L, I47A/V, G48V, I50V). To assess potential interactions between KF9-specific CTL and emergence of these important resistance mutations, we studied CTL recognition of the mutations and analyzed protease sequences in an HLA-I–typed patient cohort. METHODS: CTL recognition of KF9 and resistance mutations in KF9 were studied in 38 HLA-B*1501-positive HIV-1–infected patients using variant KF9 peptides in interferon-g enzyme-linked immunospot assays. Protease sequences were analyzed in 302 HLA-I–typed HIV-1–infected patients. RESULTS:G48V abolished KF9 recognition by CTL in all patients. Furthermore, M46I, I47A, and I50V could impair or abolish CTL recognition in many patients. In contrast, M46L and I47V showed good CTL recognition in nearly all patients. HIV-1 protease sequence analysis showed no statistical correlation between the occurrence of resistance mutations in KF9 and HLA-B*1501. Viral load in patients failing therapy with KF9 mutations was significantly lower in HLA-B*1501-positive patients in comparison with HLA-B*1501-negative patients. CONCLUSIONS: PI mutations, G48V, M46I, and I47A, can abrogate CTL recognition, indicating potential interactions between development of drug resistance and CTL response. However, we could not find evidence that development of these PI mutations is influenced by KF9-specific CTL.
Authors: Jeffrey I Boucher; Troy W Whitfield; Ann Dauphin; Gily Nachum; Carl Hollins; Konstantin B Zeldovich; Ronald Swanstrom; Celia A Schiffer; Jeremy Luban; Daniel N A Bolon Journal: Mol Biol Evol Date: 2019-04-01 Impact factor: 16.240
Authors: Stephane Champiat; Rui André Saraiva Raposo; Nicholas J Maness; John L Lehman; Sean E Purtell; Aaron M Hasenkrug; Jacob C Miller; Hansi Dean; Wayne C Koff; Marisa Ailin Hong; Jeffrey N Martin; Steven G Deeks; Gerald E Spotts; Christopher D Pilcher; Fredrick M Hecht; Esper G Kallas; Keith E Garrison; Douglas F Nixon Journal: PLoS One Date: 2012-06-29 Impact factor: 3.240
Authors: Marieke Pingen; Annemarie M J Wensing; Katrien Fransen; Annelies De Bel; Dorien de Jong; Andy I M Hoepelman; Emmanouil Magiorkinis; Dimitrios Paraskevis; Maja M Lunar; Mario Poljak; Monique Nijhuis; Charles A B Boucher Journal: Retrovirology Date: 2014-11-29 Impact factor: 4.602