Long-Read Deep Sequencing Reveals High Rates of Multilineage Transmission and Rapid Viral Population Changes in Acute HIV Infection

Mullins, J. I.; Deng, W.; Giorgi, E. E.; Magaret, C. A.; Rolland, M.; Bhattacharaya, T.; Westfall, D. H.; Yssel, A. E. J.; Bumgarner, R. E.; Murrell, B.; Ndungu, T.; Robb, M. L.; Rossenkhan, R.; Edlefsen, P. T.; Dong, K. L.; Chen, L.; Gwashu-Nyangiri, A.; Zhao, H.; Thebus, R.; Sawe, F.; Nitayaphan, S.; York, T.; Matten, D.; Murrell, H.; Pankow, A. P.; Juraska, M.; Ludwig, J.; Hural, J.; Cohen, M. S.; Corey, L.; McElrath, M. J.; Gilbert, P. B.; Williamson, C.

doi:10.1101/2025.10.15.682663

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bioRxiv · 10.1101/2025.10.15.682663

Long-Read Deep Sequencing Reveals High Rates of Multilineage Transmission and Rapid Viral Population Changes in Acute HIV Infection

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Abstract

Understanding the selective forces acting upon HIV early in infection is crucial to design prevention strategies. By leveraging deep sequencing and the short diagnostic intervals of the FRESH and RV217 cohorts (median 4 days) between the last-negative and first-positive RNA tests, we captured a precise and early snapshot of acute HIV infection. The frequency of multiple transmitted viruses of 38% in these as well as placebo recipients from the AMP trials was higher than previously published, with the true frequency likely to be higher. The relative abundance of lineages fluctuated substantially over time in two-thirds of the multilineage infections, generating uncertainty in identifying the specific viruses that were transmitted and founding the infection. Viral populations exhibited diversity and selection on the Gag and Env proteins at the earliest times examined, with sites inferred to be undergoing negative selection most evident. These data may help explain vaccination failures and provide new targets for prevention.

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Mullins, J. I., Deng, W., Giorgi, E. E., Magaret, C. A., Rolland, M., Bhattacharaya, T., Westfall, D. H., Yssel, A. E. J., Bumgarner, R. E., Murrell, B., Ndungu, T., Robb, M. L., Rossenkhan, R., Edlefsen, P. T., Dong, K. L., Chen, L., Gwashu-Nyangiri, A., Zhao, H., Thebus, R., Sawe, F., Nitayaphan, S., York, T., Matten, D., Murrell, H., Pankow, A. P., Juraska, M., Ludwig, J., Hural, J., Cohen, M. S., Corey, L., McElrath, M. J., Gilbert, P. B., Williamson, C.. 2025-10-15. Long-Read Deep Sequencing Reveals High Rates of Multilineage Transmission and Rapid Viral Population Changes in Acute HIV Infection. https://doi.org/10.1101/2025.10.15.682663

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