Ultrasensitive single-genome sequencing reveals strong purifying selection in acute HIV- 1 infection

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ABSTRACT HIV transmission from one individual to another occurs by one or a small number of virions followed by spread and genetic diversification into a complex quasispecies. To understand the early events in this process, we investigated how HIV-1 genomes diversify within the first two to three weeks after transmission by use of ultra-deep single subgenomic sequencing of over 10,000 plasma RNA genomes in each of a cohort of 15 individuals in acute infection. This approach confirmed transmission of one or a few transmitted/founder (TF) viral lineages and very limited early divergence from the founder sequences. Most observed variants that differed from the TF included single nucleotide changes attributable to HIV-1 reverse transcriptase (RT) error or host APOBEC3G/F activity. Comparing the number of expected versus observed changes after transmission indicated that most de novo mutations do not persist in the virus population, consistent with strong purifying selection. We found little evidence that early diversification is driven by reversions to subtype consensus or by cytotoxic T lymphocyte pressure, although rare multi-mutation lineages suggest occasional influences. Together, these findings indicate that early HIV-1 evolution is influenced by stochastic and host-mediated mutational processes ( e.g. , APOBEC3G/F) filtered by strong purifying selection. The strong purifying selection observed in the early weeks of HIV-1 infection may provide an opportunity to investigate the potential of new interventions to induce viremic control, such as combinations of broadly neutralizing antibodies, cellular immunotherapy, or mRNA therapeutic vaccination. AUTHOR SUMMARY When a person acquires HIV, especially through sexual transmission, infection is usually established by just one or a few viral variants. However, over the early months and years of infection, these viral variants accumulate mutations until almost no two viral genomes are identical in a typical sample. Here, we sequenced tens of thousands of viral variants in the early weeks after transmission to understand the early events that contribute to this vast viral diversification. We found that the accumulation of mutations was slower than expected, implying a selection against HIV-1 diversification in acute infection, potentially leaving a window of low genetic diversity for the study of new interventions towards inducing viremic control, such as immunotherapy or mRNA vaccination. Of the early viral mutations that were observed, many were induced by host enzymes, rather than from errors by the viral enzyme used for replication. Our results provide more context for understanding HIV evolution and provide a deep sampling of viral diversity after transmission.

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