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

Gillman, A. N.; Birler, C. M.; Vujjini, R. R.; Fili, M.; McCarthy-Potter, S. A.; Chen, W.; Broghammer, M. M.; Hu, G.; Gartland, M. J.; Prakash, M.; Helverson, A.; Brown, G. D.; Haim, H.

doi:10.64898/2025.12.27.696684

bioRxiv · 10.64898/2025.12.27.696684

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

Gillman, A. N.·Birler, C. M.·Vujjini, R. R.·Fili, M.·McCarthy-Potter, S. A.·Chen, W.·Broghammer, M. M.·Hu, G.·Gartland, M. J.·Prakash, M.·Helverson, A.·Brown, G. D.·Haim, H.

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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 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 in vivo. On-treatment mutation frequencies correlated with their spontaneous emergence rates in temsavir-untreated individuals, and were governed by two parameters: (i) Probability of mutation appearance, determined by number and type of nucleotide changes required, and (ii) 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.

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Gillman, A. N., Birler, C. M., Vujjini, R. R., Fili, M., McCarthy-Potter, S. A., Chen, W., Broghammer, M. M., Hu, G., Gartland, M. J., Prakash, M., Helverson, A., Brown, G. D., Haim, H.. 2025-12-27. Comprehensive Mapping of the Virus and Host Factors that Guide the Paths of HIV-1 Escape from a Therapeutic. https://doi.org/10.64898/2025.12.27.696684

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