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- Title
Factors influencing estimates of HIV-1 infection timing using BEAST.
- Authors
Dearlove, Bethany; Tovanabutra, Sodsai; Owen, Christopher L.; Lewitus, Eric; Li, Yifan; Sanders-Buell, Eric; Bose, Meera; O'Sullivan, Anne-Marie; Kijak, Gustavo; Miller, Shana; Poltavee, Kultida; Lee, Jenica; Bonar, Lydia; Harbolick, Elizabeth; Ahani, Bahar; Pham, Phuc; Kibuuka, Hannah; Maganga, Lucas; Nitayaphan, Sorachai; Sawe, Fred K.
- Abstract
While large datasets of HIV-1 sequences are increasingly being generated, many studies rely on a single gene or fragment of the genome and few comparative studies across genes have been done. We performed genome-based and gene-specific Bayesian phylogenetic analyses to investigate how certain factors impact estimates of the infection dates in an acute HIV-1 infection cohort, RV217. In this cohort, HIV-1 diagnosis corresponded to the first RNA positive test and occurred a median of four days after the last negative test, allowing us to compare timing estimates using BEAST to a narrow window of infection. We analyzed HIV-1 sequences sampled one week, one month and six months after HIV-1 diagnosis in 39 individuals. We found that shared diversity and temporal signal was limited in acute infection, and insufficient to allow timing inferences in the shortest HIV-1 genes, thus dated phylogenies were primarily analyzed for env, gag, pol and near full-length genomes. There was no one best fitting model across participants and genes, though relaxed molecular clocks (73% of best fitting models) and the Bayesian skyline (49%) tended to be favored. For infections with single founders, the infection date was estimated to be around one week pre-diagnosis for env (IQR: 3–9 days) and gag (IQR: 5–9 days), whilst the genome placed it at a median of 10 days (IQR: 4–19). Multiply-founded infections proved problematic to date. Our ability to compare timing inferences to precise estimates of HIV-1 infection (within a week) highlights that molecular dating methods can be applied to within-host datasets from early infection. Nonetheless, our results also suggest caution when using uniform clock and population models or short genes with limited information content. Author summary: Molecular dating using phylogenetics allows us to estimate the date of an infection from time-stamped within-host sequences alone. There are large datasets of HIV-1 sequences, but genome and gene analyses are not often performed in parallel and rarely with the possibility to compare results against a known narrow window of infection. We showed that all but the longest genes are near-clonal in acute infection, with little information for dating purposes. For infections with single founders, we estimated the eclipse phase—the time between HIV-1 exposure and the first positive diagnostic test—to last between one and two weeks using env, gag, pol and near full-length genomes. This approach could be used to narrow the date of suspected infection in ongoing clinical trials for the prevention of HIV-1 infection.
- Subjects
HIV; MOLECULAR clock; GENES; BAYESIAN analysis; TIME management; INFECTION
- Publication
PLoS Computational Biology, 2021, Vol 17, Issue 2, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1008537