A Novel Mechanism of HIV Drug Resistance Encoded in p6Gag
S. PETERS*, M. MUNOZ, R. MARTINEZ, G. BLEIBER, A. CIUFFI, P. MEYLAN, and A. TELENTI.
Ctr. Hosp. Univ. Vaudois, Lausanne, Switzerland
Background: Development of resistance to antiretrovirals (ART) may involve mutations mapping away from the viral protease and reverse transcriptase. We analysed p6Gagpolymorphisms occurring under ART.
Methods: We analysed p6Gag sequences of viruses from 140 patients treated or naive to ART. Relevant polymorphisms were incorporated in viral constructs for analysis of infectivity by single-round infection experiments, replication by infection kinetics, viral assembly by SDS-PAGE, and drug susceptibility assays.
Results: A significant degree of p6Gag polymorphism, comprising deletions and insertions, was observed. A duplication in the PTAPP motif (most frequently PTAPPAPP) was found in 28/114 (25%) of samples from individuals failing ART, but was absent in samples from 29 treatment-naive individuals and 14 instances of primary infection. It was found to be the first mutation selected under treatment in some cases. Introduction of this duplication in a HIV wild type background resulted in an infectious and replication-competent virus. Preliminary analysis suggests a delayed and diminished production of early viral proteins and particles without significant defect in maturation. Constructs are being tested for resistance to ART.
Conclusions: p6Gag PTAPP motif is critical for packaging of pol -encoded enzymes, maturation, budding and particle size. Duplication in the p6 motif PTAPP, exclusively observed under drug selective pressure, represents a potential novel mechanism of resistance.
Key Words: p6, Pol-packaging, Resistance