Concealed for a Long Time on the Marches of Empires: Hepatitis B Virus Genotype I

Abstract

Genotype I, the penultimate HBV genotype to date, was granted the status of a bona fide genotype only in the XXIst century after some hesitations. The reason for these hesitations was that genotype I is a complex recombinant virus formed with segments from three original genotypes, A, C, and G. It was estimated that genotype I is responsible for only an infinitesimal fraction (<1.0%) of the chronic HBV infection burden worldwide. Furthermore, most probably due to its recent discovery and rarity, the natural history of infection with genotype I is poorly known in comparison with those of genotypes B or C that predominate in their area of circulation. Overall, genotype I is a minor genotype infecting ethnic minorities. It is endemic to the Southeast Asian Massif or Eastern Zomia, a vast mountainous or hilly region of 2.5 million km² spreading from Eastern India to China, inhabited by a little more than 100 million persons belonging primarily to ethnic minorities speaking various types of languages (Tibeto-Burman, Austroasiatic, and Tai-Kadai) who managed to escape the authority of central states during historical times. Genotype I consists of two subtypes: I1, present in China, Laos, Thailand, and Vietnam; and I2, encountered in India, Laos, and Vietnam.

Keywords: Guangxi; HBV; Hepadnaviridae; Southeast Asian Massif; Zomia; ethnic minorities; genotype I; recombinant.

Figure 1

Genetic composition of HBV genotype I according to SimPlot (A) and jpHMM (B). Colors of original genotypes are conserved in both figures (A: red, C: green, and G: purple). Analysis by SimPlot was not performed using a reference sequence comparison. We preferred, instead, to proceed with a bulk analysis that considers, for each genotype, the set of full-length sequences mentioned on Figure 2. Parameters used were those already employed by [8].

Figure 2

Circle cladogram of HBV genotypes. The two subtypes and genotype I are clearly differentiated. In total, 121 full-length genomes of HBV genotype I have been included. Other HBV genotypes (A–H,J) are differentiated by colors. The circle cladogram was generated on MEGA XI using the maximum likelihood method and Tamura-Nei 2-parameter model with 1000 bootstrap iterations. Bootstrap values are mentioned for the main nodes.

Figure 3

Hypothetical reconstruction of genotype I emergence. The hypothetical first event of recombination associated a genotype A strain and a genotype G strain to remove the non-functional HBeAg of genotype G. Then, a second event of recombination brought the more efficient enhancer 2, basal core promoter, pre-core, and core gene of a genotype C isolate. Color code from Figure 1 is preserved (A: red, C: green, and G: purple).

Figure 4

HBV genotype I genome and its open reading frames. The table below recapitulates the composition of each ORF regarding each original genotype that participated in viral genesis.

Figure 5

Geographic distribution of genotype I in continental Asia. Independent countries and subnational geographical entities where genotype I has been isolated are colored. Other territories are left in grey. The approximate limits of Southeast Asian Massif, also called Zomia by anthropologists, are materialized by a dotted yellow line. The I subtypes of HBV isolated in a given territory are mentioned.

Figure 6

Dendrogram including 121 full sequences of genotype I. Subtypes I1 and I2 are well-differentiated. Within I1 branch appears a large cluster of I1 strains from Guangxi, which form a homogeneous group with much more nucleotide variations than other strains. The tree was generated as in Figure 2 and transformed with Dendroscope-3 to account for more precision of the evolutionary dynamics affecting some genotype I strains. Bootstrap values are mentioned for the main nodes.