Global Origin and Spatiotemporal Spread of Hepatitis C Virus Epidemic Genotypes/Subtypes: A Complete Genome-Based Phylodynamic and Phylogeographic Analyses

Abstract

Hepatitis C virus (HCV) is a pathogenic virus of global health concern. The phylodynamics of HCV genotypes/subtypes 1a, 1b, 2, and 3 are explored only for specific geographic regions. However, their genome based global origin and detailed spatiotemporal spread, have yet to be extensively studied. To study the global evolution of "epidemic" HCV genotypes/subtypes, we screened all available HCV complete genome sequences (n = 2744) from 27 countries worldwide for over four decades. We used representative sequences (n = 516) for phylodynamic and phylogeographic analyses, examining HCV worldwide origin, transmission, and spatiotemporal spread. We are the first to study the global phylogeography of genotype 2. The evolutionary rates for genotype/subtype 1a, 1b, 2, and 3 are 1.109 × 10^-3, 1.096 × 10^-3, 5.013 × 10^-3 and 1.483 × 10^-3 substitutions/site/year respectively. We deduced tMRCAs and origin location of respective HCV genotype/subtype as 1909.21 (United States), 1893.36 (Japan), 981.76 (France), and 1714.89 (India). We estimated their migration pattern with time to and from different continents. The origin location of genotype 2 was estimated to be France instead of previous postulated African origin. This can be related to slave trade, French colonization, and previous studies on specific geographic regions only. HCV genotypes/subtypes showed transmission and expansion due to factors like World War II, iatrogenic infections, "baby boomer" population, inefficient medical screening, intravenous drug use, decline due to antiviral therapy introduction. Our study provides novel and extensive information about the evolutionary history and spatiotemporal spread of the HCV genotypes responsible for most infections worldwide.

Keywords: HCV; epidemiology; evolution; migration; phylogenetic; spatiotemporal; transmission.