title: Transmembrane protein polymorphisms and resistance to T-20 (Enfuvirtide, Fuzeon) in HIV-1 infected therapy-naive seroconverters and AIDS patients under HAART-T-20 therapy.
abstract: The human immunodeficiency virus type 1 fusion inhibitor T-20 (Enfuvirtide, Fuzeon) has recently been introduced into clinical practice. T-20 in combination with HAART efficiently inhibits HIV-1 replication, however T-20 resistance has been reported and the number of confirmed resistant-associated mutations is growing. In this study we aimed to analyze HIV-1 gp41 transmembrane protein (TM) variability and primary resistance to T-20 in plasma viruses from 10 HIV-1 subtype B infected homosexuals. Nine out of ten were documented seroconverters. Nine individuals (including one long time infected therapy naïve individual) were part of four linked virus infection chains. We also examined TM polymorphism in two AIDS patients under HAART and T-20 therapy. Obtained TM amplicons were examined for minor variants by clonal analysis.Sequences polymorphism of the N-terminal regions of the fusion domain (FD) and the heptad repeat 2 (HR2) domain were demonstrated in examined seroconverters. Analysis of the heptad repeat 1 (HR1) domain revealed T-20 resistance in cloned sequences from 3/10 individuals. In two individuals these mutations were present as minor viral quasispecies. Transmission of the resistant virus to the sexual partner was traced in virus infection chain.Baseline TM amplicons (population sequence) and clones from two patients under HAART did not contain T-20 resistance associated mutations. After onset of T-20 therapy only resistant viruses were identified in plasma from the patients. As shown by clonal analysis of plasma from one patient, treatment interruption results in viruses reverting to a T-20-sensitive genotype.
authors: HIV Variabilitat und moleculare Epidemiologie/P11, Robert Koch-Institut, 20 Nordufer, 13353, Berlin, Germany. Morozov@umbi.umd.edu
authors: Vladimir A
authors: VA
authors: Morozov
authors: Alexei V
authors: AV
authors: Morozov
authors: Dirk
authors: D
authors: Schürmann
authors: Dirck
authors: D
authors: Schürmann
authors: Heiko
authors: H
authors: Jessen
authors: Claudia
authors: C
authors: Kücherer
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000595:Amino Acid Sequence; D023241:Antiretroviral Therapy, Highly Active; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D006679:HIV Seropositivity; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D008565:Membrane Proteins; D010446:Peptide Fragments; D000077560:Enfuvirtide