Single-Genome Sequencing of Hepatitis C Virus in Donor-Recipient Pairs Distinguishes Modes and Models of Virus Transmission and Early Diversification
- Hui Lia,
- Mark B. Stoddarda,
- Shuyi Wanga,
- Elena E. Giorgib,
- Lily M. Blairb,c,
- Gerald H. Learna,
- Beatrice H. Hahna,
- Harvey J. Alterd,
- Michael P. Busche,
- Daniel S. Fiererf,
- Ruy M. Ribeirob,
- Alan S. Perelsong,
- Tanmoy Bhattacharyab,h and
- George M. Shawa
- aDepartments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- bT-Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
- cDepartment of Biology, Stanford University, Stanford, California, USA
- dDepartment of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland, USA
- eBlood Systems Research Institute, University of California San Francisco, San Francisco, California, USA
- fDivision of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- gTheoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
- hSanta Fe Institute, Santa Fe, New Mexico, USA
- J.-H. J. Ou, Editor
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FIG 1HCV sequence diversity in acutely infected human subject 110069. A maximum-likelihood (ML) mid-point rooted phylogenetic tree (A) and Highlighter plots (C and D) of nearly full length plasma vRNA sequences spanning the initial 6-month infection period are depicted. Plasma viral load kinetics (B) are also depicted, and the sequences are color coded to correspond to sampling time points determined from the first vRNA-positive/antibody-negative time point (blue, day 2; red, day 17; green, day 142). One month earlier, the HCV vRNA and antibody tests were negative. HCV antibody tests were negative through day 17 but were positive at the next sampled time point on day 146. The tree and the Highlighter plot reveal productive clinical infection by four T/F viruses (T/F lineages 1 to 4). Viral diversity is indicated by the scale bar and bootstrap values are shown. In the Highlighter (C), tick marks are color coded to indicate nucleotide substitutions by A (green), T (red), C (blue), or G (orange) compared to the consensus sequence of the first time point (TP1). In panel D, tick marks denote synonymous (green) or nonsynonymous (red) substitutions.
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FIG 2HCV plasma vRNA kinetics and 5′ half genome HCV sequences from an epidemiologically linked human HCV transmission pair. (A) Viral load profiles in the presumed donor (patient 1 [BGI]) and recipient (patient 2 [CCI]) are illustrated. The sampling time points are circled and color coded red (donor) and blue (recipient). (B) ML phylogenetic trees and Highlighter plots show that each subject was productively infected by a single virus. (C) The combined tree and plot show that the T/F viral genomes infecting both subjects were identical in sequence.
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FIG 3HCV viral load kinetics and sequences from a human-to-chimpanzee transmission pair. (A) Viral load kinetics in acutely infected human subject 10081. Red and black circles indicate plasma samples subjected to sequence analysis. (B) Fifty milliliters of 10081 plasma from the day −4 time point was infused intravenously into chimpanzee X355 at week 0. Plasma vRNA kinetics are indicated by filled black dots, with blue and green circles indicating time points subjected to sequence analysis. Alanine aminotransferase (ALT) is a hepatic enzyme that when elevated above baseline indicates liver inflammation or injury. An ML phylogenetic tree (with sequences color coded red, black, blue, and green to correspond to time points indicated in panels A and B) and a Highlighter plot show that the human subject 10081 was acutely infected by multiple viruses, one of which, H1 (top of panel C), was transmitted to chimpanzee X355 giving rise to the C1 T/F lineage. Note that the T/F genome corresponding to H1 is identical in sequence to the T/F genome corresponding to the C1 lineage.
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FIG 4
HCV viral load kinetics and sequences in a human-to-chimpanzee transmission pair. (A) Viral load kinetics in acutely infected human subject 10083. Red and black circles indicate plasma samples subjected to sequence analysis. (B) Fifty milliliters of 10083 plasma from the day zero time point was infused intravenously into chimpanzee X331 at week 0. Plasma vRNA kinetics are indicated by filled dots, with blue, purple, and green circles indicating time points subjected to sequence analysis. ALT values are shown. (C) An ML phylogenetic tree (with sequences color-coded red and black to correspond to time points indicated in panel A) and a Highlighter plot show that the human subject 10083 was acutely infected by multiple viruses. The model described by Bhattacharya and coworkers (14; http://www.santafe.edu/~tanmoy/programs/HCV/) suggests a minimum of 12 T/F genomes (H1-H12). Panel D depicts sequences (color coded blue, purple, and green to correspond to time points indicated in panel B) from chimpanzee X331, and the Bhattacharya model suggests a minimum of 10 T/F viruses (C1 to C10). (E) Human (red and black) and chimpanzee (blue, purple, and green) sequences are combined. (F) An ML tree of sequences found to be identical between the human donor and the chimpanzee recipient. This tree reveals 13 T/F genome lineages (C1 to C13′) that were transmitted unaltered from humans to chimpanzees. These 13 transmitted genomes are enclosed in black ovals in panel D and include three lineages (C11′, C12′, and C13′) that were identified empirically (F) but not by the Bhattacharya clustering analysis (D).
- Copyright © 2015 Li et al.
