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

Sep 29, 2026

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HIV-1 resistance to therapeutics can emerge through diverse mutational routes, yet the determinants guiding pathway selection in vivo remain unclear. Through comprehensive screening, the study identified 18 Env mutations that enhance resistance to the FDA-approved small-molecule temsavir. Only a subset appeared in vivo, and on-treatment mutation frequencies matched spontaneous emergence in temsavir-untreated individuals. Two governing parameters were quantified: mutation appearance and persistence shaped by Env function and immune fitness. Non-neutralizing antibodies restricted escape route diversity, driving convergence.

LanguageEnglish

CategoryHealthcare

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ABSTRACT

INTRODUCTION

bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.27.696684](https://doi.org/10.64898/2025.12.27.696684); this version posted December 27, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Comprehensive Mapping of the Virus and Host Factors that Guide the Paths of HIV-1 2 Escape from a Therapeutic 3 4 Aaron N Gillman 1‡, Cassian M Birler1‡, Rohith Rao Vujjini1‡, Mohammad Fili2 , Samuel A 5 McCarthy-Potter1 , Wilson Chen3 , Madeline M Broghammer1 , Guiping Hu2 , Margaret J Gartland3 , 6 Manyu Prakash4 , Annika Helverson5 , Grant Brown5 , and Hillel Haim 1\# . 7 8 1 Department of Microbiology and Immunology, The University of Iowa, Iowa City, IA. 9 2 Department of Systems Engineering and Operations Research, George Mason University, 10 Fairfax, VA. 11 3 ViiV Healthcare, Research Triangle Park, North Carolina, USA. 12 4 ViiV Healthcare, Brentford , United Kingdom. 13 5 Department of Biostatistics, School of Public Health, The University of Iowa, Iowa City, IA. 14 15 ‡ These authors contributed equally to this work. 16 17 \# To whom correspondence should be addressed: 18 Hillel Haim, MD, PhD 19 Department of Microbiology and Immunology 20 The University of Iowa 21 51 Newton Rd, 3-540 BSB 22 Iowa City, IA 52242 23 Email: [Hillel-haim@uiowa.edu](Hillel-haim@uiowa.edu) [24](24 Phone:)[ Phone:](24 Phone:) (319) 335-9989 25 26 Keywords: Antiviral therapeutics, HIV-1, Virus escape, Envelope glycoproteins, Virus Evolution, 27 Selection Pressures, Virus fitness , Fostemsavir, BMS-626529 . bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.27.696684](https://doi.org/10.64898/2025.12.27.696684); this version posted December 27, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 28 ABSTRACT 29 HIV-1 resistance to therapeutics can emerge through diverse mutational routes, yet the 30 determinants guiding pathway selection in vivo remain unclear. Through comprehensive 31 screening, we identified 18 mutations in the HIV-1 Env protein that enhance resistance to the 32 FDA-approved small-molecule therapeutic temsavir. We then examined their occurrence in HIV- 33 infected individuals who developed resistance on therapy. Only a subset of the resistance- 34 enhancing mutations emerged in vivo. On-treatment mutation frequencies correlated with their 35 spontaneous emergence rates in temsavir-untreated individuals, and were governed by two 36 parameters: (i) Probability of mutation appearance, determined by number and type of nucleotide 37 changes required, and (ii) Probability of mutation persistence, determined by Env functional and 38 immune fitness. Notably, non-neutralizing antibodies commonly-elicited in HIV-infected 39 individuals restricted emergence of multiple resistant forms , driving convergence to a narrow set 40 of escape routes. These findings establish a quantitative framework for predicting therapeutic 41 resistance and reveal how host-immunity constrains viral evolution during treatment. bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.27.696684](https://doi.org/10.64898/2025.12.27.696684); this version posted December 27, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 42 INTRODUCTION 43 Human immunodeficiency virus type 1 (HIV-1) has a remarkable ability to adapt to the 44 host environment. Due to the low fidelity of the viral replication machin

FAQs

What did the study identify regarding HIV-1 escape from temsavir?

Comprehensive screening identified 18 mutations in the HIV-1 Env protein that enhance resistance to temsavir.

Why did only a subset of resistance-enhancing mutations emerge in vivo?

Only some mutations that enhance resistance also arose and persisted in infected individuals, indicating constraints from functional and immune fitness.

How were appearance and persistence of mutations quantitatively related?

On-treatment mutation frequencies correlated with spontaneous emergence rates in temsavir-untreated individuals, governed by the probability of mutation appearance and the probability of mutation persistence.

Sep 29, 2026

Uploaded by Bulrr