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Massively Parallel Profiling of HIV-1 Resistance to the Fusion Inhibitor Enfuvirtide

1
Basic Sciences and Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2
Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
3
Howard Hughes Medical Institute, Seattle, WA 98109, USA
*
Authors to whom correspondence should be addressed.
Viruses 2019, 11(5), 439; https://doi.org/10.3390/v11050439
Received: 19 April 2019 / Revised: 9 May 2019 / Accepted: 12 May 2019 / Published: 15 May 2019
(This article belongs to the Section Antivirals & Vaccines)
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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. View Full-Text
Keywords: HIV-1 drug resistance; enfuvirtide; T-20; fusion inhibitor; HIV-1 envelope; deep mutational scanning HIV-1 drug resistance; enfuvirtide; T-20; fusion inhibitor; HIV-1 envelope; deep mutational scanning
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Dingens, A.S.; Arenz, D.; Overbaugh, J.; Bloom, J.D. Massively Parallel Profiling of HIV-1 Resistance to the Fusion Inhibitor Enfuvirtide. Viruses 2019, 11, 439.

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