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A non-parametric analytic framework for within-host viral phylogenies and a test for HIV-1 founder multiplicity.

ABSTRACT: Phylogenetics is a powerful tool for understanding the diversification dynamics of viral pathogens. Here we present an extension of the spectral density profile of the modified graph Laplacian, which facilitates the characterization of within-host molecular evolution of viruses and the direct comparison of diversification dynamics between hosts. This approach is non-parametric and therefore fast and model-free. We used simulations of within-host evolutionary scenarios to evaluate the efficiency of our approach and to demonstrate the significance of interpreting a viral phylogeny by its spectral density profile in terms of diversification dynamics. The key features that are captured by the profile are positive selection on the viral gene (or genome), temporal changes in substitution rates, mutational fitness, and time between sampling. Using sequences from individuals infected with HIV-1, we showed the utility of this approach for characterizing within-host diversification dynamics, for comparing dynamics between hosts, and for charting disease progression in infected individuals sampled over multiple years. We furthermore propose a heuristic test for assessing founder heterogeneity, which allows us to classify infections with single and multiple HIV-1 founder viruses. This non-parametric approach can be a valuable complement to existing parametric approaches.

SUBMITTER: Lewitus E

PROVIDER: S-EPMC6826062 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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A non-parametric analytic framework for within-host viral phylogenies and a test for HIV-1 founder multiplicity.

Lewitus Eric E Rolland Morgane M

Virus evolution 20190701 2

Phylogenetics is a powerful tool for understanding the diversification dynamics of viral pathogens. Here we present an extension of the spectral density profile of the modified graph Laplacian, which facilitates the characterization of within-host molecular evolution of viruses and the direct comparison of diversification dynamics between hosts. This approach is non-parametric and therefore fast and model-free. We used simulations of within-host evolutionary scenarios to evaluate the efficiency ...[more]

PMID: 31700680

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Project description:Transmission of multiple founder variants has been associated with faster HIV disease progression. Many studies have attempted to determine the number of founder variants, mainly by analysis of sequence diversity and/or tree topology from acutely HIV-infected individuals. We hypothesized that adding sequence data collected from source partners might improve resolution and characterization of transmission events. Blood plasma samples were collected from both the source and recipient in thirty epidemiologically- and phylogenetically linked transmission pairs. All were men who have sex with men, sampled on average 70 days (range 11-170) after the recipient's estimated date of infection. Next generation sequencing (454 FLX, Roche) of HIV-1 env (C2-V3) was performed for all samples. Inspection of sequence alignments, highlighter plots, phylogenetic tree topologies and sequence diversity were used to determine the multiplicity of founder viruses with and without the inclusion of source data. Using only recipient sequence data, we were able to resolve multiplicity in twenty-six of the thirty transmission pairs (87 percent). Among them, five presented with a high viral diversity at baseline (>0.10 subst/site), consistent with multiple founders. By incorporating sequence data collected from the source partner, we were able to characterize all thirty transmission pairs. Overall, sixteen transmission events (53.3 percent) involved multiple founders. Results obtained by combining sequence data from recipient and source were congruent for nineteen of the twenty-six (73 percent) cases where conclusions were made using only recipient sequence data. The multiplicity of founders was associated with significantly higher HIV RNA levels (P = 0.04). To further evaluate the transmission bottleneck, we focused on single founder transmissions (fourteen of the thirty), and identified four recipients (28.6 percent) that had founder variants that were inferred to arise from minority viral populations in the source. These source clades ranged from 1.0 to 5.4 percent of the sampled population. Incorporating sequence data from the source increased of the ability to determine the multiplicity of founder variants, reduced misclassification, and allowed us to infer the transmission of minority variants.

Dataset Information

A non-parametric analytic framework for within-host viral phylogenies and a test for HIV-1 founder multiplicity.

Publications

A non-parametric analytic framework for within-host viral phylogenies and a test for HIV-1 founder multiplicity.

Similar Datasets

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