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A framework including recombination for analyzing the dynamics of within-host HIV genetic diversity.

ABSTRACT: This paper presents a novel population genetic model and a computationally and statistically tractable framework for analyzing within-host HIV diversity based on serial samples of HIV DNA sequences. This model considers within-host HIV evolution during the chronic phase of infection and assumes that the HIV population is homogeneous at the beginning, corresponding to the time of seroconversion, and evolves according to the Wright-Fisher reproduction model with recombination and variable mutation rate across nucleotide sites. In addition, the population size and generation time vary over time as piecewise constant functions of time. Under this model I approximate the genealogical and mutational processes for serial samples of DNA sequences by a continuous coalescent-recombination process and an inhomogeneous Poisson process, respectively. Based on these derivations, an efficient algorithm is described for generating polymorphisms in serial samples of DNA sequences under the model including various substitution models. Extensions of the algorithm are also described for other demographic scenarios that can be more suitable for analyzing the dynamics of genetic diversity of other pathogens in vitro and in vivo. For the case of the infinite-sites model, I derive analytical formulas for the expected number of polymorphic sites in sample of DNA sequences, and apply the developed simulation and analytical methods to explore the fit of the model to HIV genetic diversity based on serial samples of HIV DNA sequences from 9 HIV-infected individuals. The results particularly show that the estimates of the ratio of recombination rate over mutation rate can vary over time between very high and low values, which can be considered as a consequence of the impact of selection forces.

SUBMITTER: Sargsyan O

PROVIDER: S-EPMC3917834 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A framework including recombination for analyzing the dynamics of within-host HIV genetic diversity.

Sargsyan Ori O

PloS one 20140207 2

This paper presents a novel population genetic model and a computationally and statistically tractable framework for analyzing within-host HIV diversity based on serial samples of HIV DNA sequences. This model considers within-host HIV evolution during the chronic phase of infection and assumes that the HIV population is homogeneous at the beginning, corresponding to the time of seroconversion, and evolves according to the Wright-Fisher reproduction model with recombination and variable mutation ...[more]

PMID: 24516557

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Project description:BackgroundStudying within-host genetic diversity of Mycobacterium tuberculosis (Mtb) in patients during treatment may identify adaptations to antibiotic and immune pressure. Understanding the significance of genetic heteroresistance, and more specifically heterozygous resistance-associated variants (RAVs), is clinically important given increasing use of rapid molecular tests and whole genome sequencing (WGS).MethodsWe analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (>75%) had baseline rifampicin resistance. Sputum was collected for culture at baseline and at between two and nine intervals until month six. Positive cultures underwent WGS. Mixed infections and reinfections were excluded from analysis.FindingsBaseline Mtb overall genetic diversity (at treatment initiation or major change to regimen) was associated with cavitary disease, not taking antiretroviral therapy if HIV infected, infection with lineage 2 strains and absence of second-line drug resistance on univariate analyses. Baseline genetic diversity was not associated with six-month outcome. Genetic diversity increased from baseline to weeks one and two before returning to previous levels. Baseline genetic heteroresistance was most common for bedaquiline (6/10 [60%] of isolates with RAVs) and fluoroquinolones (9/62 [13%]). Most patients with heterozygous RAVs on WGS with sequential isolates available demonstrated RAV persistence or fixation (17/20, 85%). New RAVs emerged in 9/286 (3%) patients during treatment. We could detect low-frequency RAVs preceding emergent resistance in only one case, although validation of deep sequencing to detect rare variants is required.InterpretationIn this study of single-strain Mtb infections, baseline within-host bacterial genetic diversity did not predict outcome but may reveal adaptations to host and drug pressures. Predicting emergent resistance from low-frequency RAVs requires further work to separate transient from consequential mutations.FundingWellcome Trust, NIH/NIAID.

Dataset Information

A framework including recombination for analyzing the dynamics of within-host HIV genetic diversity.

Publications

A framework including recombination for analyzing the dynamics of within-host HIV genetic diversity.

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