Mixed cytomegalovirus genotypes in HIV-positive mothers show compartmentalization and distinct patterns of transmission to infants

Pang, Juanita; Slyker, Jennifer A.; Roy, Sunando; Bryant, Josephine M.; Atkinson, Claire; Cudini, Juliana; Farquhar, Carey; Griffiths, Paul; Kiarie, James; Morfopoulou, Sofia; Roxby, Alison C.; Tutil, Helena; Williams, Rachel; Gantt, Soren; Goldstein, Richard A.; Breuer, Judith

doi:10.7554/elife.63199

Cited by 18 publications

(23 citation statements)

References 56 publications

(82 reference statements)

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“…Four strains are not included due to the low quality such as frameshift errors in many genes. Six samples contain two strains and thus we also tested HaROLD on them because HaROLD was adopted by another study to reconstruct HCMV strains in clinical samples [ 52 ]. The result is shown in Table 6 .…”

Section: Resultsmentioning

confidence: 99%

“…These samples are sequenced at different time points from the mother’s breast milk (BM), cervical (CV), and the infant’s blood spots (BS). In a recent study [ 52 ], the authors used HaROLD to reconstruct and analyze the HCMV strains in this batch of samples. Here, we take a similar approach to the original study to show the utility of VirStrain in identifying mixed strain infections.…”

Section: Resultsmentioning

confidence: 99%

“…All HCMV mock datasets are downloaded from [ 51 ] (NCBI BioProject: PRJEB32127). All HCMV mix-strain datasets are downloaded from [ 52 ] (NCBI BioProject: PRJNA605798).…”

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confidence: 99%

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VirStrain: a strain identification tool for RNA viruses

2022

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Viruses change constantly during replication, leading to high intra-species diversity. Although many changes are neutral or deleterious, some can confer on the virus different biological properties such as better adaptability. In addition, viral genotypes often have associated metadata, such as host residence, which can help with inferring viral transmission during pandemics. Thus, subspecies analysis can provide important insights into virus characterization. Here, we present VirStrain, a tool taking short reads as input with viral strain composition as output. We rigorously test VirStrain on multiple simulated and real virus sequencing datasets. VirStrain outperforms the state-of-the-art tools in both sensitivity and accuracy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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VirStrain: a strain identification tool for RNA viruses

2022

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“…The added benefit of examining whole genome is that linked mutations can be identified statistically using an approach that we gave recently developed 29 . Indeed haplotype reconstruction has proved beneficial in the analysis of compartmentalisation and diversification of several RNA viruses, including HIV-1, CMV and SARS-CoV-2 30,48,49 . Key findings of this study were: firstly that diversity increased over time with variable trajectory away from the consensus baseline sequence and also the reconstructed ancestral subtype M consensus.…”

Section: Discussionmentioning

confidence: 99%

“…We are confident that the combination of computational analyses has provided a detailed understanding of viral dynamics under nonsuppressive ART and is directly applicable to wider datasets. The method used to reconstruct viral haplotypes in silico is novel and has previously been validated in HIV-positive participants with CMV 48 .…”

Section: Discussionmentioning

confidence: 99%

HIV-1 evolutionary dynamics under non-suppressive antiretroviral therapy

Kemp

Charles

Derache

et al. 2021

Preprint

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Background: Viral population dynamics in long term viraemic antiretroviral therapy (ART) treated individuals have not been well characterised. Prolonged virologic failure on 2nd-line protease inhibitor (PI) based ART without emergence of major protease mutations is well recognised, providing an opportunity to study within-host evolution. Methods: Using next-generation Illumina short read sequencing and in silico haplotype reconstruction we analysed whole genome sequences from longitudinal plasma samples of eight chronically infected HIV-1 individuals failing 2nd-line regimens from the ANRS 12249 TasP trial, in the absence of high frequency major PI resistance mutations. Plasma drug levels were measured by HPLC. Three participants were selective for in-depth variant and haplotype analyses, each with five or more timepoints spanning at least 16 months. Results: During PI failure synonymous mutations were around twice as frequent as non-synonymous mutations across participants. Prior to or during exposure to PI, we observed several polymorphic amino acids in gag (e.g. T81A, T375N) which are have also been previously associated with exposure to protease inhibitor exposure. Although overall SNP frequency at abundance above 2% appeared stable across time in each individual, divergence from the consensus baseline sequence did increase over time. Non-synonymous changes were enriched in known polymorphic regions such as env whereas synonymous changes were more often observed to fluctuate in the conserved pol gene. Phylogenetic analyses of whole genome viral haplotypes demonstrated two common features: Firstly, evidence for selective sweeps following therapy switches or large changes in plasma drug concentrations, with hitchhiking of synonymous and non-synonymous mutations. Secondly, we observed competition between multiple viral haplotypes that intermingled phylogenetically alongside soft selective sweeps. The diversity of viral populations was maintained between successive timepoints with ongoing viremia, particularly in env. Changes in haplotype dominance were often distinct from the dynamics of drug resistance mutations in reverse transcriptase (RT), indicating the presence of softer selective sweeps and/or recombination. Conclusions: Large fluctuations in variant frequencies with diversification occur during apparently "stable" viremia on non-suppressive ART. Reconstructed haplotypes provided further evidence for sweeps during periods of partial adherence, and competition between haplotypes during periods of low drug exposure. Drug resistance mutations in RT can be used as markers of viral populations in the reservoir and we found evidence for loss of linkage disequilibrium for drug resistance mutations, indicative of recombination. These data imply that even years of exposure to PIs, within the context of large stable populations displaying ongoing selective competition, may not precipitate emergence of major PI resistance mutations, indicating significant fitness costs for such mutations. Ongoing viral diversification within reservoirs may compromise the goal of sustained viral suppression.

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