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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. [ABSTRACT FROM AUTHOR]

Most HIV-1 infected individuals do not know their infection dates. Precise infection timing is crucial information for studies that document transmission networks or drug levels at infection. To improve infection timing, we used the prospective RV217 cohort where the window when plasma viremia becomes detectable is narrow: the last negative visit occurred a median of four days before the first detectable HIV-1 viremia with an RNA test, referred below as diagnosis. We sequenced 1,280 HIV-1 genomes from 39 participants at a median of 4, 32 and 170 days post-diagnosis. HIV-1 infections were dated by using sequence-based methods and a viral load regression method. Bayesian coalescent and viral load regression estimated that infections occurred a median of 6 days prior to diagnosis (IQR: 9–3 and 11–4 days prior, respectively). Poisson-Fitter, which analyzes the distribution of hamming distances among sequences, estimated a median of 7 days prior to diagnosis (IQR: 15–4 days) based on sequences sampled 4 days post-diagnosis, but it did not yield plausible results using sequences sampled at 32 days. Fourteen participants reported a high-risk exposure event at a median of 8 days prior to diagnosis (IQR: 12 to 6 days prior). These different methods concurred that HIV-1 infection occurred about a week before detectable viremia, corresponding to 20 days (IQR: 34–15 days) before peak viral load. Together, our methods comparison helps define a framework for future dating studies in early HIV-1 infection. Author summary: HIV-1 infected individuals rarely know when they became infected but knowing when an infection occurred provides critical information regarding HIV-1 pathogenesis and epidemiology. Using a unique cohort in which infection was known to have occurred in a narrow interval, we investigated methods to estimate the timing of infections. Several methods suggested that HIV-1 infection typically occurs a median of one week before the infection can be detected by HIV-1 RNA testing. Going forward, we provide a strategy that can be used to elucidate the origin of an acute/early infection. [ABSTRACT FROM AUTHOR]

HIV-1 disseminates to a broad range of tissue compartments during acute HIV-1 infection (AHI). The central nervous system (CNS) can serve as an early and persistent site of viral replication, which poses a potential challenge for HIV-1 remission strategies that target the HIV reservoir. CNS compartmentalization is a key feature of HIV-1 neuropathogenesis. Thus far, the timing of how early CNS compartmentalization develops after infection is unknown. We examined whether HIV-1 transmitted/founder (T/F) viruses differ between CNS and blood during AHI using single-genome sequencing of envelope gene and further examined subregions in pol and env using next-generation sequencing in paired plasma and cerebrospinal fluid (CSF) from 18 individuals. Different proportions of mostly minor variants were found in six of the eight multiple T/F-infected individuals, indicating enrichment of some variants in CSF that may lead to significant compartmentalization in the later stages of infection. This study provides evidence for the first time that HIV-1 compartmentalization in the CNS can occur within days of HIV-1 exposure in multiple T/F infections. Further understanding of factors that determine enrichment of T/F variants in the CNS, as well as potential long-term implications of these findings for persistence of HIV-1 reservoirs and neurological impairment in HIV, is needed. [ABSTRACT FROM AUTHOR]

An abstract of the article "Cryptic Multiple HIV-1 Infection Revealed by Early, Frequent, and Deep Sampling during Acute Infection" by Gustavo Hernan Kijak, Eric Sanders-Buell, Agnes-Laurance Chenine and colleagues is presented.

An abstract of the article "No Selection for Env with Shorter Variable Loops in Acute HIV-1 Infection" by Morgane Rolland, Sodsai Tovanabutra, Eric Sanders-Buell and colleagues is presented.