We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Massively Parallel Profiling of HIV-1 Resistance to the Fusion Inhibitor Enfuvirtide.
- Authors
Dingens, Adam S.; Arenz, Dana; Overbaugh, Julie; Bloom, Jesse D.
- Abstract
Identifying drug resistance mutations is important for the clinical use of antivirals and can help define both a drug's mechanism of action and the mechanistic basis of resistance. Resistance mutations are often identified one-at-a-time by studying viral evolution within treated patients or during viral growth in the presence of a drug in cell culture. Such approaches have previously mapped resistance to enfuvirtide, the only clinically approved HIV-1 fusion inhibitor, to enfuvirtide's binding site in the N-terminal heptad repeat (NHR) of the Envelope (Env) transmembrane domain as well as a limited number of allosteric sites. Here, we sought to better delineate the genotypic determinants of resistance throughout Env. We used deep mutational scanning to quantify the effect of all single-amino-acid mutations to the subtype A BG505 Env on resistance to enfuvirtide. We identified both previously characterized and numerous novel resistance mutations in the NHR. Additional resistance mutations clustered in other regions of Env conformational intermediates, suggesting they may act during different fusion steps by altering fusion kinetics and/or exposure of the enfuvirtide binding site. This complete map of resistance sheds light on the diverse mechanisms of enfuvirtide resistance and highlights the utility of using deep mutational scanning to comprehensively map potential drug resistance mutations.
- Subjects
ENFUVIRTIDE (Drug); DRUG resistance; VIRAL mutation; ANTIVIRAL agents; ALLOSTERIC regulation; BINDING sites
- Publication
Viruses (1999-4915), 2019, Vol 11, Issue 5, p439
- ISSN
1999-4915
- Publication type
Article
- DOI
10.3390/v11050439