Global Identification of Three Major Genotypes of Varicella-Zoster Virus: Longitudinal Clustering and Strategies for Genotyping

Abstract

By analysis of a single, variable, and short DNA sequence of 447 bp located within open reading frame 22 (ORF22), we discriminated three major varicella-zoster virus (VZV) genotypes. VZV isolates from all six inhabited continents that showed nearly complete homology to ORF22 of the European reference strain Dumas were assigned to the European (E) genotype. All Japanese isolates, defined as the Japanese (J) genotype, were identical in the respective genomic region and proved the most divergent from the E strains, carrying four distinct variations. The remaining isolates carried a combination of E-and J-specific variations in the target sequence and thus were collectively termed the mosaic (M) genotype. Three hundred twenty-six isolates collected in 27 countries were genotyped. A distinctive longitudinal distribution of VZV genotypes supports this approach. Among 111 isolates collected from European patients, 96.4% were genotype E. Consistent with this observation, approximately 80% of the VZV strains from the United States were also genotype E. Similarly, genotype E viruses were dominant in the Asian part of Russia and in eastern Australia. M genotype viruses were strongly dominant in tropical regions of Africa, Indochina, and Central America, and they were common in western Australia. However, genotype M viruses were also identified as a minority in several countries worldwide. Two major intertypic variations of genotype M strains were identified, suggesting that the M genotype can be further differentiated into subgenotypes. These data highlight the direction for future VZV genotyping efforts. This approach provides the first simple genotyping method for VZV strains in clinical samples.Varicella-zoster virus (VZV) is a human herpesvirus that commonly causes chicken pox (varicella), usually in young children. Following primary infection a lifelong latent infection is established, and the virus often reactivates in adulthood or senescence to cause shingles (zoster). The VZV genome consists of 125 kb of linear, double-stranded DNA comprising one long and one short unique region, each flanked by inverted repeats (10), and five internal repeat regions (R1 to R5) have been identified. The VZV genome contains at least 71 open reading frames (ORFs), and the functions of many of the proteins they encode have been characterized (10).During the past 2 decades, several groups attempted to evaluate VZV phylogeny. Early efforts in VZV typing used DNA restriction fragment length polymorphism (RFLP) analysis (13,37,38), an approach that confirmed the identity of the VZV strain that causes varicella on primary infection and later reactivates to cause zoster. Relatively consistent restriction enzyme digestion profiles for different VZV strains were observed, providing the first evidence that VZV has a highly conserved genome. Intrastrain variation in restriction enzyme fragment profiles among wild-type VZV isolates was observed (22,36,37). However, the most prominent differences were linked to variation in the number and composi...

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“…PCR amplifications of the ORF21 -502 bp target region, ORF22 -447 bp target region, ORF50 -514 bp target region were performed with a GeneAmp PCR System 9700 (Applied Biosystems, Carlsbad, CA) using 5 μl of DNA extracted from skin lesions of the patient. PCR products were separated on 4% precast gradient polyacrylamide gels prestained with ethidium bromide (Invitrogen) and visualized under UV irradiation alongside a 100-bp ladder (Invitrogen) [7][8][9]11,12 . Similar methods were used for multi-locus DNA sequence analysis at ORF 1,6, 9 and 28.…”

“…Several studies have demonstrated a distinctive geographic distribution of the major VZV genotypes aligning with cool versus warm climate regions of the globe 6 . It is unclear whether the strain distribution is actually driven by climate or/and other factors, such as immigration patterns [7][8][9] .…”

“…For no clear reasons, seasonality does not occur in tropical countries, and a larger proportion of people enter adulthood uninfected by VZV (ref. 7 ). Several studies have demonstrated a distinctive geographic distribution of the major VZV genotypes aligning with cool versus warm climate regions of the globe 6 .…”

“…Thus, utilizing these markers, the VZV strains can be categorized as vaccine or wildtype strains and the wild-type strains can be subsequently differentiated into distinct genotypes such as E1 or E2 (European), J (Japanese) or M1 -M4 (mosaic) (ref. 7 ). The E genotypes are the most prevalent genotype in the United States, Canada, Europe, and eastern Australia.…”

“…The E genotypes are the most prevalent genotype in the United States, Canada, Europe, and eastern Australia. The J genotype is typically found in Japan and Asia.The M genotypes are prevalent mostly in tropical countries, including Panama, Costa Rica, Barbados, Sudan, New Zealand, western part of Australia [7][8][9] .…”