TY - JOUR
T1 - Genomic characterization of hepatitis C virus transmitted founder variants with deep sequencing
AU - on behalf of the InC3 Study Group
AU - Abayasingam, Arunasingam
AU - Leung, Preston
AU - Eltahla, Auda
AU - Bull, Rowena A.
AU - Luciani, Fabio
AU - Grebely, Jason
AU - Dore, Gregory J.
AU - Applegate, Tanya
AU - Page, Kimberly
AU - Bruneau, Julie
AU - Cox, Andrea L.
AU - Kim, Arthur Y.
AU - Schinkel, Janke
AU - Shoukry, Naglaa H.
AU - Lauer, Georg M.
AU - Maher, Lisa
AU - Hellard, Margaret
AU - Prins, Maria
AU - Lloyd, Andrew
AU - Rodrigo, Chaturaka
N1 - Funding Information:
The infrastructure for sharing of data and specimens in InC3 was funded by the National Institute on Drug Abuse (NIDA) R01DA031056 . The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of NIDA or the National Institutes of Health (NIH). Research support for the InC3 cohorts includes: the Netherlands National Institute for Public Health and the Environment to the Amsterdam Cohort Study (ACS); Baltimore Before and After Study (BBA) - National Institutes of Health ( NIH U19 AI088791 ); Boston Acute HCV Study: transmission, immunity, outcomes network (BAHSTION) is funded under NIH NIAID U19 U19 AI066345 ; ATAHC – NIDA RO1 DA 15999-01; HITS-p - National Health and Medical Research Council of Australia (NHMRC) - Project No. 222887, Partnership No. 1016351, Program Nos. 510488 and 1053206; HITS-c – UNSW Hepatitis C Vaccine Initiative and NHMRC Project Grant No. 630483 ; Networks/MIX – NHMRC Project Grants Nos. 331312 and 545891 and the Victorian Operational Infrastructure Support Programme (Department of Health, Victoria, Australia); HepCo - the Canadian Institutes of Health Research ( MOP-103138 and MOP-106468 ); UFO – NIH R01 DA016017. The following InC3 investigators are funded by research fellowships: NHMRC, Australia – JG, MH, LM, GD, ARL; Fonds de la Recherche du Québec, Canada – JB and NHS.
Funding Information:
The infrastructure for sharing of data and specimens in InC3 was funded by the National Institute on Drug Abuse (NIDA) R01DA031056. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of NIDA or the National Institutes of Health (NIH). Research support for the InC3 cohorts includes: the Netherlands National Institute for Public Health and the Environment to the Amsterdam Cohort Study (ACS); Baltimore Before and After Study (BBA) - National Institutes of Health (NIH U19 AI088791); Boston Acute HCV Study: transmission, immunity, outcomes network (BAHSTION) is funded under NIH NIAIDU19 U19 AI066345; ATAHC – NIDA RO1 DA 15999-01; HITS-p - National Health and Medical Research Council of Australia (NHMRC) - Project No. 222887, Partnership No. 1016351, Program Nos. 510488 and 1053206; HITS-c – UNSW Hepatitis C Vaccine Initiative and NHMRC Project Grant No. 630483; Networks/MIX – NHMRC Project Grants Nos. 331312 and 545891 and the Victorian Operational Infrastructure Support Programme (Department of Health, Victoria, Australia); HepCo - the Canadian Institutes of Health Research (MOP-103138 and MOP-106468); UFO – NIH R01 DA016017. The following InC3 investigators are funded by research fellowships: NHMRC, Australia – JG, MH, LM, GD, ARL; Fonds de la Recherche du Québec, Canada – JB and NHS.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/7
Y1 - 2019/7
N2 - Transfer of hepatitis C virus (HCV) infection from a donor to a new recipient is associated with a bottleneck of genetic diversity in the transmitted viral variants. Existing data suggests that one, or very few, variants emerge from this bottleneck to establish the infection (transmitted founder [T/F] variants). In HCV, very few T/F variants have been characterized due to the challenges of obtaining early infection samples and of high throughput viral genome sequencing. This study used a large, acute HCV, deep-sequenced dataset from first viremia samples collected in nine prospective cohorts across four countries, to estimate the prevalence of single T/F viruses, and to identify host and virus-related factors associated with infections initiated by a single T/F variant. The short reads generated by Illumina sequencing were used to reconstruct viral haplotypes with two haplotype reconstruction algorithms. The haplotypes were examined for random mutations (Poisson distribution) and a star-like phylogeny to identify T/F viruses. The findings were cross-validated by haplotype reconstructions across three regions of the genome (Core-E2, NS3, NS5A) to minimize the possibility of spurious overestimation of single T/F variants. Of 190 acute infection samples examined, 54 were very early acute infections (HCV antibody negative, RNA positive), and single transmitted founders were identified in 14 (26%, 95% CI: 16–39%) after cross validation across multiple regions of the genome with two haplotype reconstruction algorithms. The presence of a single T/F virus was not associated with any host or virus-related factors, notably viral genotype or spontaneous clearance. In conclusion, approximately one in four new HCV infections originates from a single T/F virus. Resolution of genomic sequences of single T/F variants is the first step in exploring unique properties of these variants in the infection of host hepatocytes.
AB - Transfer of hepatitis C virus (HCV) infection from a donor to a new recipient is associated with a bottleneck of genetic diversity in the transmitted viral variants. Existing data suggests that one, or very few, variants emerge from this bottleneck to establish the infection (transmitted founder [T/F] variants). In HCV, very few T/F variants have been characterized due to the challenges of obtaining early infection samples and of high throughput viral genome sequencing. This study used a large, acute HCV, deep-sequenced dataset from first viremia samples collected in nine prospective cohorts across four countries, to estimate the prevalence of single T/F viruses, and to identify host and virus-related factors associated with infections initiated by a single T/F variant. The short reads generated by Illumina sequencing were used to reconstruct viral haplotypes with two haplotype reconstruction algorithms. The haplotypes were examined for random mutations (Poisson distribution) and a star-like phylogeny to identify T/F viruses. The findings were cross-validated by haplotype reconstructions across three regions of the genome (Core-E2, NS3, NS5A) to minimize the possibility of spurious overestimation of single T/F variants. Of 190 acute infection samples examined, 54 were very early acute infections (HCV antibody negative, RNA positive), and single transmitted founders were identified in 14 (26%, 95% CI: 16–39%) after cross validation across multiple regions of the genome with two haplotype reconstruction algorithms. The presence of a single T/F virus was not associated with any host or virus-related factors, notably viral genotype or spontaneous clearance. In conclusion, approximately one in four new HCV infections originates from a single T/F virus. Resolution of genomic sequences of single T/F variants is the first step in exploring unique properties of these variants in the infection of host hepatocytes.
KW - Hepatitis C virus
KW - InC3 study
KW - Next generation sequencing
KW - People who inject drugs
KW - Transmitted-founder virus
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U2 - 10.1016/j.meegid.2019.02.032
DO - 10.1016/j.meegid.2019.02.032
M3 - Article
C2 - 30853512
AN - SCOPUS:85063032152
VL - 71
SP - 36
EP - 41
JO - Infection, Genetics and Evolution
JF - Infection, Genetics and Evolution
SN - 1567-1348
ER -