TY - JOUR T1 - Estimating time of HIV-1 infection from next-generation sequence diversity JF - bioRxiv DO - 10.1101/129387 SP - 129387 AU - Vadim Puller AU - Richard Neher AU - Jan Albert Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/21/129387.abstract N2 - Estimating the time since infection (TI) in newly diagnosed HIV-1 patients is challenging, but important to understand the epidemiology of the infection. Existing biomarkers for the recent infection are relatively imprecise. Here we explore the utility of virus diversity estimated by next-generation sequencing (NGS) as novel biomarker by using a recent genome-wide longitudinal dataset obtained from 11 untreated HIV-1-infected patients with known dates of infection.Virus diversity increased linearly with time, particularly at 3rd codon positions, with little inter-patient variation. The precision of the TI estimate improved with increasing sequencing depth, showing the superiority of NGS over counting polymorphic sites in Sanger sequences, which is one of the alternative biomarkers. The full advantage of the high sequencing resolution of NGS was utilized with continuous diversity measures, average Hamming distance or site entropy, rather than the fraction of polymorphic sites. The precision depended on the genomic region and codon position and was highest when 3rd codon positions in the entire pol gene was used. For these data TI estimates had a mean absolute error of around 1 year. The error increased only slightly from around 0.6 years at a TI of 6 months to around 1.1 year at 6 years. In addition, NGS diversity compared favorably with other biomarkers for binary classification of patients as being recently or long-term infected.Our results show that virus diversity determined by NGS can be used to estimate time since HIV-1 infection with a precision that is better than most alternative biomarkers. Importantly, TI can be estimated many years after infection. We provide regression coefficients that can be used for TI estimation.Author summary HIV-1 establishes a chronic infection, which may last for many years before the infected person is diagnosed. The resulting uncertainty in the date of infection leads to difficulties in estimating the number of infected but undiagnosed persons as well as the number of new infections, which is necessary for developing appropriate public health policies and interventions. Such estimates would be much easier if the time since HIV-1 infection for newly diagnosed cases could be accurately estimated. Three types of biomarkers have been shown to contain information about the time since HIV-1 infection, but unfortunately they only distinguish between recent and long-term infections (concentration of HIV-1-specific antibodies) or are too imprecise (immune status as measured by levels of CD4+ T-lymphocytes and viral sequence diversity). In this paper we show that recent advances in sequencing technologies, i.e. the development of next generation sequencing, enable significantly more precise determination of the time since HIV-1 infection, even many years after the infection event. This is a significant advance which could translate into more effective HIV-1 prevention. ER -