Abstract
In Lao PDR, where more than 8% of the population are chronic carriers of HBsAg, multiple genotypes and subgenotypes co-circulate and are prone to generate recombinant viruses. Phylogenetic analyses of multiple clones per donor revealed mixed infections of subgenotypes B1, B2, B4, C1, C5, I1 and I2 in almost 6% of HBsAg positive rejected blood donors. Recombination analyses and distance calculations furthermore showed that about 65% (17/26) of the mixed infected donors showed recombinations in the S-gene alone, involving the predominant genotypes B and C. These results suggest that, at least in Laos, hepatitis B virus (HBV) mixed infections lead to frequent recombinations. In many donors with recombinant strains, the recombinant fragment and a non-recombinant strain of the same genotype co-existed (127/185 analysed recombinant fragments). For a large proportion of these (60/127), the most closely related known virus was found, although not always exclusively, in the same donor. Recombinant virus strains are largely distinct. This is reflected in an unexpected diversity in recombination breakpoints and the relatively rare recombinations with identical recombination patterns of the same genotypes in different donors. Recent recombination events would explain the limited spread of each of the recombinants. Using a published mutation rate of 4.2×10−5 mutations per site and year, the observed minimum genetic distances of 0–0.60% between parent strain and recombinant fragment would correspond to 0–71 years of evolution from a most recent common ancestor (MRCA). Thus several lines of evidence are suggestive of recent independent recombination events, a proportion of these even occurring within the same donors. In conclusion, our analyses revealed a high variability of mixed infections as a very probable breeding ground of multiple variable recombination events in Laos that so far have not led to new dominant strains.
Highlights
Hepatitis B virus (HBV), a major global public health burden, is classified into 8 recognised genotypes A-H [1,2] and a tentative genotype I found in Laos [3], Vietnam [4,5,6] and in Northwestern China [7] and India [8]
Subgenotype C3 consists of strains from Oceania, C4 of strains exclusively from Australia and subgenotype C5 strains have been reported from the Philippines, Indonesia, Vietnam and Laos [3,4,18,19]
Our study revealed an unusual cauldron of mixed infections as a breeding ground of multiple and highly variable recombination events that so far have not led to new dominant strains
Summary
Hepatitis B virus (HBV), a major global public health burden, is classified into 8 recognised genotypes A-H [1,2] and a tentative genotype I found in Laos [3], Vietnam [4,5,6] and in Northwestern China [7] and India [8]. While B1 (formerly Bj) is mainly found in Japan and represents the non-recombined B subgenotype [12], subgenotypes B2 to B4 (formerly Ba) largely originate from mainland Asia and are recombinants with genotype C. According to the nomenclature from Huy et al [11], subgenotype C1 represents predominantly strains from mainland Asia (Laos, Vietnam, Thailand and Myanmar), while C2 is prevalent in Japan, Hong Kong, China and Korea [2,10,11,17]. Subgenotype C3 consists of strains from Oceania, C4 of strains exclusively from Australia and subgenotype C5 strains have been reported from the Philippines, Indonesia, Vietnam and Laos [3,4,18,19]. Subgenotypes C6 to C10 have been proposed recently for strains from the Philippines and Indonesia [3,19,20]
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