Journal article
Comprehensive mapping of the virus and host factors that guide the paths of HIV-1 escape from a therapeutic
Cell reports (Cambridge), Vol.45(7), 117558
07/28/2026
DOI: 10.1016/j.celrep.2026.117558
PMID: 42322610
Abstract
HIV-1 resistance to therapeutics can emerge through diverse mutational routes, yet the determinants guiding pathway selection in vivo remain unclear. Through comprehensive screening, we identify 18 mutations in the HIV-1 Env protein that enhance resistance to the FDA-approved small-molecule therapeutic temsavir. We then examine their occurrence in HIV-infected individuals who developed resistance on therapy. Interestingly, only a subset of the resistance-enhancing mutations emerged in vivo. On-treatment mutation frequencies correlate with their emergence rates in temsavir-untreated individuals and are governed by two parameters: (1) probability of mutation appearance, determined by the number and type of nucleotide changes required, and (2) probability of mutation persistence, determined by Env functional and immune fitness. Notably, non-neutralizing antibodies commonly elicited in HIV-infected individuals restrict 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.
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•Systematic screen maps multiple HIV-1 Env mutations conferring resistance to temsavir•In vivo, resistance converges on a limited set of pathways•On-treatment frequencies parallel mutation rates in untreated individuals•Emergence is governed by mutation probability, virus fitness, and immune constraints
Gillman et al. systematically screen for HIV-1 Env mutations that confer resistance to the FDA-approved therapeutic temsavir (BMS-626529). They discovered that in treated individuals, resistance mutations converge to limited pathways determined by mutation probability, viral fitness, and conserved host immune pressures, providing a framework to predict evolutionary outcomes during therapy.
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 IowaCassian M. Birler - University of IowaRohith Rao Vujjini - University of IowaMohammad Fili - George Mason UniversitySamuel A. McCarthy-Potter - University of IowaWilson Chen - ViiV Healthcare, Durham, NC, USAMadeline M. Broghammer - University of IowaGuiping Hu - George Mason UniversityMargaret J. Gartland - ViiV Healthcare, Durham, NC, USAManyu Prakash - ViiV Healthcare (United Kingdom)Annika Helverson - University of IowaGrant G. Brown - University of Iowa, BiostatisticsHillel Haim - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.45(7), 117558
- DOI
- 10.1016/j.celrep.2026.117558
- PMID
- 42322610
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Grant note
- National Institutes of Health (NIH): AI170205 ViiV Healthcare Investigator Sponsored Study: AI170205, 4104
This work was supported by National Institutes of Health (NIH) grant R01 AI170205 to H.H. and by ViiV Healthcare Investigator Sponsored Study (ID 4104) to H.H. The funders played no role in study design, data analysis, in vitro data acquisition or analysis, or the decision to publish this work. The authors are grateful to Anthony Roberth Rojas Chavez for assistance with processing of the sequence data.
- Language
- English
- Date published
- 07/28/2026
- Academic Unit
- Microbiology and Immunology; Biostatistics
- Record Identifier
- 9985176757502771
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