Comprehensive Mapping of the Virus and Host Factors that Guide the Paths of HIV-1 Escape from a Therapeutic

Aaron N Gillman; Cassian M Birler; Rohith Rao Vujjini; Mohammad Fili; Samuel A McCarthy-Potter; Wilson Chen; Madeline M Broghammer; Guiping Hu; Margaret J Gartland; Manyu Prakash; Annika Helverson; Grant Brown; Hillel Haim

doi:10.64898/2025.12.27.696684

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Comprehensive Mapping of the Virus and Host Factors that Guide the Paths of HIV-1 Escape from a Therapeutic

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Comprehensive Mapping of the Virus and Host Factors that Guide the Paths of HIV-1 Escape from a Therapeutic

Aaron N Gillman, Cassian M Birler, Rohith Rao Vujjini, Mohammad Fili, Samuel A McCarthy-Potter, Wilson Chen, Madeline M Broghammer, Guiping Hu, Margaret J Gartland, Manyu Prakash, …

bioRxiv

Cold Spring Harbor Laboratory

12/27/2025

DOI: 10.64898/2025.12.27.696684

PMCID: PMC12767509

PMID: 41497656

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https://doi.org/10.64898/2025.12.27.696684View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

HIV-1 resistance to therapeutics can emerge through diverse mutational routes, yet the determinants guiding pathway selection remain unclear. Through comprehensive screening, we identified 18 mutations in the HIV-1 Env protein that enhance resistance to the FDA-approved small-molecule therapeutic temsavir. We then examined their occurrence in HIV-infected individuals who developed resistance on therapy. Only a subset of the resistance-enhancing mutations emerged . On-treatment mutation frequencies correlated with their spontaneous emergence rates in temsavir-untreated individuals, and were governed by two parameters: Probability of mutation appearance, determined by number and type of nucleotide changes required, and Probability of mutation persistence, determined by Env functional and immune fitness. Notably, non-neutralizing antibodies commonly-elicited in HIV-infected individuals restricted emergence of multiple resistant forms, driving convergence to a narrow set of escape routes. These findings establish a quantitative framework for predicting therapeutic resistance and reveal how host-immunity constrains viral evolution during treatment.

Fostemsavir

HIV-1

Selection Pressures

Virus escape

BMS-626529

Virus Evolution

Antiviral therapeutics

Envelope glycoproteins

Virus fitness

Details

Title: Subtitle: Comprehensive Mapping of the Virus and Host Factors that Guide the Paths of HIV-1 Escape from a Therapeutic
Creators: Aaron N Gillman - University of Iowa
Cassian M Birler - University of Iowa
Rohith Rao Vujjini - University of Iowa
Mohammad Fili - George Mason University
Samuel A McCarthy-Potter - University of Iowa
Wilson Chen - ViiV Healthcare (Spain)
Madeline M Broghammer - University of Iowa
Guiping Hu - George Mason University
Margaret J Gartland - ViiV Healthcare (Spain)
Manyu Prakash - ViiV Healthcare (United Kingdom)
Annika Helverson - University of Iowa
Grant Brown - University of Iowa
Hillel Haim - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.64898/2025.12.27.696684
PMID: 41497656
PMCID: PMC12767509
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Language: English
Date posted: 12/27/2025
Academic Unit: Microbiology and Immunology
Record Identifier: 9985116170002771

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