Evolution and world-wide distribution of varicella–zoster virus clades

Infection, Genetics and Evolution 11 (2011) 1–10

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Infection, Genetics and Evolution journal homepage: www.elsevier.com/locate/meegid

Review

Evolution and world-wide distribution of varicella–zoster virus clades Jonas Schmidt-Chanasit a,*, Andreas Sauerbrei b a b

Bernhard-Nocht-Institute for Tropical Medicine, Department of Virology, Clinical Virology Laboratory, Bernhard Nocht Strasse 74, D-20359 Hamburg, Germany Institute of Virology and Antiviral Therapy, German Reference Laboratory for HSV and VZV, Jena, Germany

A R T I C L E I N F O

A B S T R A C T

Article history: Received 8 July 2010 Received in revised form 25 August 2010 Accepted 27 August 2010 Available online 15 September 2010

Varicella–zoster virus (VZV, Human herpesvirus 3), a world-wide distributed pathogen, is the causative agent of varicella (chickenpox) and zoster (shingles). Both diseases result in significant morbidity and economic burden. The implementation of routine varicella vaccination programs in many countries may reduce significantly the incidence of varicella disease. Furthermore, vaccination against zoster can diminish the burden of zoster considerably. Although many epidemiological, clinical and laboratory studies were performed in the past decades to reveal the clinical burden as well as epidemiological features and changes of the two diseases caused by VZV, a comparatively low number of molecular epidemiological studies have been performed to investigate and monitor the genetic variability and phylogenetic relationship of VZV strains throughout the world. To date, it is well established that VZV can be divided into five major clades confirmed by full-genome sequencing and two provisional clades that have to be confirmed. Additionally, several studies have demonstrated a regional dominance of specific VZV clades, most likely in dependence on environmental factors, evolutionary conditions and host–virus interactions and/or importation of viral strains. However, there are many open questions such as the alteration of genotype distribution through immigration or travel, the introduction of the varicella vaccine strain into population and the emergence of wild-type vaccine recombinant viruses. To increase our knowledge in this field by further innovative approaches, the new common nomenclature of VZV clades established recently will be very useful. In this review, the currently available data concerning the geographic distribution and evolution of VZV clades are summarized. Different models of VZV evolution and recombination are discussed and recent changes in VZV clade distribution addressed. ß 2010 Elsevier B.V. All rights reserved.

Keywords: Clade Varicella–zoster virus Epidemiology Vaccine Recombination This review is dedicated to our scientific mentors Professor Peter Wutzler and Professor Hans-Wilhelm Doerr.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . World-wide distribution of varicella–zoster virus clades . . . . . . . . . . . . . . . . Varicella–zoster virus evolution and recombination . . . . . . . . . . . . . . . . . . . . Molecular studies of the Oka vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaccine impact, recombination and recent changes in genotype distribution Conclusion and remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Varicella–zoster virus (VZV) is a member of the family Herpesviridae. Within the genus Varicellovirus, VZV belongs to the subfamily Alphaherpesvirinae together with the herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) within the genus Simplexvirus. Typical characteristics of Alphaherpesvirinae are their short

* Corresponding author. Tel.: +49 40 42818 942; fax: +49 40 42818 941. E-mail address: [email protected] (J. Schmidt-Chanasit). 1567-1348/$ – see front matter ß 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.meegid.2010.08.014

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1 2 5 6 7 8 9

reproduction cycle, fast spreading, efficient destruction of infected cells and persistence in sensory ganglia. In contrast to HSV-1 and 2, VZV is characterized by a limited host spectrum, which includes exclusively cells of human and simian origin. Apart from these biological properties, differences between viruses are now defined on the basis of gene content and sequence similarities (Roizman et al., 1992). Like all herpesviruses, VZV is a double stranded DNA virus. Viral genome is 125 kb in size and contains at least 72 open reading frames (ORF) constituting 71 genes. Since three genes are duplicated, the genome contains 68 identified unique genes (Davison and Scott, 1986). Viral DNA genome is arranged into

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two main coding regions, unique long (UL) and unique short (US). UL region is flanked by small inverted repeats termed terminal (TRL) and internal repeats long (IRL). US region is flanked by large inverted repeats termed terminal (TRS) and internal repeats short (IRS). Five genomic regions contain tandem direct reiterations (R1– R5), which represent short sequences with a high G + C content. VZV is spread by inhalation of aerosolized virus particles (Arvin et al., 1996), which are excreted from the respiratory tract of infected persons at the end of the incubation period. In addition, the vesicle fluid in case of varicella or zoster rash is highly infectious. VZV invades the body through the mucous membranes of the respiratory tract and undergoes the first phase of replication in the regional lymph nodes. It follows a primary cell-associated viremia, during which the virus infects peripheral blood mononuclear cells, and a secondary viremia disseminating the virus to cutaneous epithelial cells. This results in the typical signs of varicella, also termed as chickenpox, including fever, severe respiratory symptoms and exanthema. Complications are rarely observed in immunocompetent infants. However, varicella is a special risk for patients with impaired cellular immune function, e.g. patients with oncological diseases, organ or bone marrow transplantation, autoimmunopathies, congenital immune defects or persons infected with human immunodeficiency virus (Arvin, 1999). The most common complications are those attributable to secondary bacterial infections, neurological and hematological manifestations. In addition, varicella during pregnancy is associated with high risk of maternal pneumonia and the congenital transmission of the virus leading to severe consequences for the fetus (Sauerbrei and Wutzler, 2007a). Varicella pneumonia has been considered the most important complication in pregnant women. By placental transmission of the virus during the first two trimesters, maternal varicella may cause the congenital varicella syndrome. Maternal infection near term is associated with a substantial risk of neonatal varicella. After primary infection, VZV establishes lifelong latency in trigeminal and dorsal root ganglia. Endogenous viral reactivation may lead to viral replication and inflammation in the ganglion. After centrifugal spreading down the sensory nerve, the virus is released in the skin, where it causes herpes zoster (shingles). Waning VZV-specific cell-mediated immunity is an important contributor to susceptibility to zoster (Gershon et al., 1997). Zoster is characterized by unilateral vesicular rash within a single cutaneous dermatome. The disease is most often localized in the thoracic region and most of the severe clinical consequences result from viral reactivation in cranial ganglia. Zoster is often complicated by pain termed as post-herpetic neuralgia if the pain persists after the rash healed (Gilden et al., 2009). Other important complications include neurological manifestations, hemorrhagic and necrotic alterations of the skin, bacterial super-infections and eye or ear involvement. Seroepidemiological studies performed in different countries with temperate climate revealed in the pre-vaccine era that the prevalence of VZV-specific IgG class antibodies showed rapid increase during the first decade of life and reached between 80% and more than 90% (Fairley and Miller, 1996; Wutzler et al., 2001). Among the more than 40 years olds, only isolated individuals were susceptible to VZV (Wutzler et al., 2001). In tropical and subtropical areas, a relatively small portion of children has been demonstrated to be VZV-seropositive and varicella has been shown to affect mainly adolescents and adults (Lokeshwar et al., 2000). Women from tropical and subtropical areas are more likely to be seronegative for VZV IgG and are, therefore, more susceptible to the development of chickenpox (Garnett et al., 1993). The differences found in VZV seroepidemiology may reflect biological distinctions of the virus and hosts as well as variations in viral transmission between temperate and tropical climates. Accord-

ingly, several studies have suggested a distinctive geographic distribution of the major VZV clades in temperate versus tropical region (Barrett-Muir et al., 2003; Loparev et al., 2007a; Quinlivan et al., 2002). In principle, the regional dominance of specific VZV clades may be dependent on environmental factors, evolutionary conditions, host–virus interactions and/or importation of viral strains through immigration or travel. Innovative approaches for the global surveillance of VZV clades are important tools to resolve these questions. In early studies, VZV DNA was characterized using restriction fragment length polymorphism (RFLP) analysis, which demonstrated inter-strain variations among wild-type isolates as well as differences between wild- and vaccine-type viruses. The RFLP markers of VZV considered most commonly in vaccine and epidemiological studies include the polymorphism of open reading frames (ORF) 38 (PstI), 54 (BglI) and 62 (SmaI) (LaRussa et al., 1992; Loparev et al., 2000; Sauerbrei et al., 2003). Thus, the majority of wild-type strains in North America and Europe were characterized as PstI+BglI, African and Asian strains were BglI+, Japanese Oka-like wild-type strains PstI+/PstIBglI+SmaI and Oka vaccine strains PstIBglI+SmaI+ (LaRussa and Gershon, 2001; Quinlivan et al., 2002; Sauerbrei and Wutzler, 2007b). Attempts to improve genotyping methods employed DNA sequencing to screen for single nucleotide polymorphisms (SNP) in different ORFs of VZV genome. Using scattered SNP method, Barrett-Muir et al. (2003) reported SNPs present in ORF 1, 21, 50 and 54 to distinguish the four main viral clades termed A, B, C and J. Similarly, Faga et al. (2001) and Wagenaar et al. (2003) analyzed the entire sequences of the five VZV glycoprotein (g) genes gH, gI, gL, gB, gE and the IE62 gene. Strains were clustered into at least four major clades designated A, B, C, and D. Loparev et al. (2004, 2007b) performed the combination of ORF 22-based genotyping plus analysis of either ORF 21 or ORF 50 to verify the presence of the five confirmed clades E1, E2, J, M1, M2 and the two provisional clades M3 and M4. In addition, VZV has been analyzed phylogenetically on the basis of full-genome sequencing (Peters et al., 2006) clustering the strains into the four major clades described by Wagenaar et al. (2003). However, this approach is not practical for all clinical specimens to be genotyped, particularly since most VZV strains cannot be propagated in cell cultures and the amount of viral DNA is limited. Finally, different nucleotide positions in ORF 51–58 were used recently by Schmidt-Chanasit et al. (2007, 2008a,b) to classify VZV wild-type strains into the five clades A, B, C, D (Faga et al., 2001; Wagenaar et al., 2003) and M1 (Loparev et al., 2007b). Since the nomenclature of VZV clades/genotypes has been based on different molecular typing methods, a new universal nomenclature has been introduced most recently separating the genotypes into five major clades (1–5) with two provisional clades (VI and VII) (Breuer et al., 2010). Using this new nomenclature, Fig. 1 demonstrates a phylogenetic network of VZV strains illustrating the evolutionary relationships between different clades. To verify the genetic diversity of VZV, the different terms genotype and clade have been used in the literature. While the definition of genotype refers to particular alleles at specified loci, a clade signifies a single ‘‘branch’’ on the phylogenetic tree. 2. World-wide distribution of varicella–zoster virus clades Several studies were performed in Europe to identify the circulating VZV clades using different approaches (Carr et al., 2004; Parker et al., 2006; Sengupta et al., 2007). However, only a few studies were included in the current review (Davison and Scott, 1986; Loparev et al., 2009, 2007a; Sauerbrei et al., 2008; SchmidtChanasit et al., 2009) because it was only possible for the selected studies to transform the data into the universal nomenclature (Breuer et al., 2010) with five major clades (1–5) and two

[(Fig._1)TD$IG]

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Fig. 1. Phylogenetic network of VZV strains based on full-genome sequences. Clade 1 includes ten strains: reference strain Dumas (NC001348), Netherlands; BC (AY548171), British Columbia, Canada; 36 (DQ479958), New Brunswick, Canada; 49 (DQ479959), New Brunswick, Canada; reference strain MSP (AY548170), Minnesota, USA; 32p5 (DQ479961), Texas, USA; Kel (DQ479954), Iowa, USA; SD (DQ479953), South Dakota, USA; NH293 (DQ674250), USA; SVETA (EU154348), Russia; clade 3 includes four strains: reference strain 03-500 (DQ479957), Alberta, Canada; 11 (DQ47995), New Brunswick, Canada; 22 (DQ479956), New Brunswick, Canada; reference strain HJO (AJ871403), Germany; clade 2 includes one strain: reference strain pOka (AB097933), Japan; clade 5 includes the reference strain CA123 strain (DQ457052), California, USA; clade 4 includes two strains: reference strain 8 (DQ479960), New Brunswick, Canada and reference strain DR (DQ452050), USA.

provisional clades (VI and VII). According to the universal nomenclature, 734 VZV strains from 19 European countries were meta-analyzed in this review. 368 (50%) strains were typed as clade 1 strains and 275 (37%) strains were typed as clade 3 strains (Table 1). Taken together, clades 1 and 3 (87%) represent the dominant clades of the circulating VZV strains in Europe (Fig. 2). In contrast, the analyzed VZV strains from Spain belong to clade 1 (48%), clade 5 (29%) and clade VI (23%) but not to clade 3 (Table 1). The higher frequencies of clades 5 and VI strains might be explained by the migration of persons with African origin to Spain (Loparev et al., 2007a). Moreover, it was suggested that the clade VI strains are recombinant strains that were established due to a recombination event of clade 1 or 3 strains with clades 4 and 5 strains (Loparev et al., 2007a). Within Europe, clade VI strains were also found frequently in France (10%) and Italy (11%) and one might speculate that clade VI strains are more common than clade 3 strains in southern Europe (Loparev et al., 2009). Interestingly, clade 5 strains were demonstrated to circulate in Germany (Sauerbrei et al., 2008) although the proportion of immigrants from Africa is relatively low when compared to Spain and France. Clade 5 strains were found to be associated only with varicella cases in Germany. Recently, a study performed to reveal the variability of the immediate early gene 62 in VZV wild-type strains demonstrated a uniform pattern of clade 5 strains and gives evidence that these strains were introduced via few sources from African countries (Sauerbrei et al., 2009). Subclades of the main circulating VZV clades 1 and 3 in Germany were identified by phylogenetic analysis of a 7482 bp stretch within the ORFs 5, 37 and 62 and by specific SNPs within the ORFs 5, 37, 56 and 62 (Schmidt-Chanasit et al., 2009). The differentiation of the main circulating VZV clades 1 and 3 revealed three different subclades (1a, 3a and 3b) circulating in Germany (Schmidt-Chanasit et al., 2009). The classification of clades 1 and 3 subclades may facilitate a more exact and in-depth monitoring of the molecular evolution of VZV in Europe and other continents where clades 1 and 3 strains are the dominant clades of the circulating VZV strains, for example in Oceania and the Americas (Fig. 2).

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Several studies were performed in the Americas to identify the circulating VZV clades using the ORF 22 method and nomenclature developed by Loparev et al. in 2004 (Sergeev et al., 2006; Dayan et al., 2004). However, this method does not discriminate clade 1 strains from clade 3 strains. Therefore, only some very recently published studies using improved typing methods (Loparev et al., 2009; Rodrı´guez-Castillo et al., 2009, 2010) or full-genome sequence analysis (Peters et al., 2006; Norberg et al., 2006; Grose et al., 2004) were included in this review. Taken together, 83 VZV strains from the US, Canada and Mexico were meta-analyzed. 58 (70%) strains were typed as clade 1 strains and 14 (17%) strains were typed as clade 3 strains (Table 1). As demonstrated for Europe, clades 1 and 3 represent dominant clades of the circulating VZV strains in the US, Canada and Mexico (Fig. 2). Presence of clades 4 and 5 strains in America (Table 1) can be explained by the immigration of people with African origin. One clade VII strain was exclusively isolated in the US in 2002 (Sergeev et al., 2006). So far, there is no evidence for the circulation of VZV clade VII strains in other parts of the world and, therefore, clade VII has not been sufficiently characterized. It would be also important to have more than one complete genomic sequence for the VZV clades 2, 5 and VII to clarify the evolution and natural history of these clades. In contrast to all other continents, the VZV clade 2 represents the dominant clade in Asia (Fig. 2). 134 strains were included in the analysis and 99 (74%) strains belong to clade 2. However, there is a striking difference in the clade distribution between the countries of the Indian subcontinent (India, Bangladesh and Nepal) and other Asian countries (China and Japan). Clade 2 strains were found not to circulate in India, Nepal and Bangladesh whereas clades 4 and 5 strains were demonstrated to be the dominant clades in these countries (Table 1). Among the analyzed VZV strains originating from Thailand, only clade 3 strains were detected (Table 1). It was suggested that clade 3 strains were introduced into the native Thai population by European immigrants that first arrived in 1511 and quickly established a permanent colony in the city of Ayutthaya (Wagenaar et al., 2003). A total of 34 African VZV strains were included in the current review. All of them belong to clade 5 (Table 1). However, it should be considered that only a few viruses have been evaluated from only four African countries. The circulation of clade 5 strains in countries with a history of African immigration (US, France and Spain) is in line with these results. The frequent detection of clade 5 strains in countries of the Indian subcontinent (India, Bangladesh and Nepal) and its evolutionary relation to African clade 5 strains needs further clarification. Sequence analysis of more than 16 kb of the VZV genome of Tanzanian VZV wild-type strains revealed putative sites within the ORFs 1, 31, 60 and 67 which show that clade 5 strains evolved through recombination of clades 1, 3 and 4 (SchmidtChanasit et al., 2008b). This is an interesting finding because it was suggested that VZV coevolves with humankind and diversified from ancestral African VZV clades into Asian (clade 2) and European (clades 1 and 3) clades (Peters et al., 2006; Wagenaar et al., 2003). Therefore, it will be important to analyze more VZV wild-type strains from different regions of Africa for a better understanding of the evolution and natural history of clade 5 strains. Because of the long history of European colonization, clades 1 and 3 strains were mainly (74%) detected in Oceania (Table 1). It was also shown that clade 3 strains currently circulating in the United Kingdom and Ireland are identical to Oceanian strains (Loparev et al., 2007b). Moreover, it was suggested that clade 3 strains may have arisen more than a century ago in Oceania through recombination events between clade 1 strains with clade 4 or 5 strains and that native Australians and native New Zealanders located to the United Kingdom and Ireland could be the source of clades 4 and 5 strains in these countries (Loparev et al., 2007b). In contrast to America and Europe, there is a substantial proportion of

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Table 1 World-wide distribution of varicella–zoster virus clades. Number of strains analyzed

Clade 1

Europe Albania Belarus Bulgaria Estonia Czech Republic Finland France Germany

734 20 15 38 3 15 28 19 442

368 17 12 34 3 7 10 12 166

(50%) (85%) (80%) (89%) (100%) (47%) (36%) (64%) (38%)

5 (1%) 0 0 0 0 0 0 0 5 (1%)

Greece Iceland Italy Latvia Lithuania Netherlands Poland Romania Russia Spain Ukraine Africa DRC Tanzania Chad Morocco Oceania Australia

3 17 17 9 5 1 4 4 57 31 6 34 20 8 5 1 243 205

3 1 11 8 4 1 2 2 55 15 5 0 0 0 0 0 128 103

(100%) (6%) (65%) (89%) (80%) (100%) (50%) (50%) (97%) (48%) (83%)

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 21 (9%) 21 (10%)

0 15 4 1 1 0 2 2 2 0 1 0 0 0 0 0 54 46

New Zealand America Canada Mexico US Asia China Bangladesh India Japan

38 83 7 68 8 134 19 7 16 79

25 58 3 50 5 0 0 0 0 0

0 0 0 0 0 99 (74%) 19 (100%) 0 0 77 (98%)

8 14 3 11 0 2 0 0 0 0

5 6 2

0 0 0

Nepal Singapore Thailand

(52%) (50%) (66%) (70%) (43%) (73%) (64%)

Clade2

0 3 (50%) 0

Clade 3 275 3 3 4 0 8 18 2 209

(37%) (15%) (20%) (11%) (53%) (64%) (10%) (47%)

(88%) (24%) (11%) (20%) (50%) (50%) (3%) (17%)

(22%) (23%) (21%) (17%) (43%) (15%) (2%)

0 0 2 (100%)

Clade 4

Clade 5

Clade VI

Clade VII

5 (1%) 0 0 0 0 0 0 1 (6%) 3 (1%)

70 (9%) 0 0 0 0 0 0 2 (10%) 59 (13%)

11 (2%) 0 0 0 0 0 0 2 (10%) 0

0 0 0 0 0 0 0 0 0

0 1 (6%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 12 (5%) 12 (6%)

0 0 0 0 0 0 0 0 0 9 0 34 20 8 5 1 24 19

0 2 1 0 1 15 0 0 10 1

5 7 0 6 1 18 0 7 6 1

(2%) (14%) (12%) (11%)

(63%) (1%)

4 (80%) 0 0

(29%) (100%) (100%) (100%) (100%) (100%) (10%) (9%) (13%) (9%) (10%) (12%) (13%) (100%) (37%) (1%)

1 (20%) 3 (50%) 0

0 0 2 0 0 0 0 0 0 7 0 0 0 0 0 0 4 4

(11%)

(23%)

(2%) (2%)

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 1 (1%) 0 1 (2%) 0 0 0 0 0 0

0 1 (1%) 0 0 1 (12%) 0 0 0 0 0

0 0 0

0 0 0

References

Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2007a) Sauerbrei et al. (2008, submitted) and Schmidt-Chanasit et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Davison and Scott (1986) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2009) Loparev et al. (2007a) Loparev et al. (2009) Loparev et al. (2004, 2009) Schmidt-Chanasit et al. (2008b) Loparev et al. (2004) Loparev et al. (2004) Toi and Dwyer (2010) and Loparev et al. (2007b) Loparev et al. (2007b) Peters et al. (2006) Rodrı´guez-Castillo et al. (2009, 2010) Loparev et al. (2009) Liu et al. (2009) Loparev et al. (2004) Loparev et al. (2004) Inoue et al. (2010) and Loparev et al. (2004) Loparev et al. (2004) Wagenaar et al. (2003) Wagenaar et al. (2003)

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Continent and country

[(Fig._2)TD$IG]

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Fig. 2. Map showing distribution of VZV clades for all five continents based on data from studies cited in Table 1.

clade 2 strains (10%) circulating in Australia (Table 1). This can be explained with migration of persons with Asian origin to Australia. Interestingly, a large proportion of the analyzed VZV strains in the current review belong to senior Australian patients with zoster, indicating that clades 1, 2, 3, 4 and 5 strains were in circulation during the first half of the 20th century. However, it will be important to analyze the association of VZV clades with the ethnic groups in Oceania for a better understanding of the natural history of VZV clades in Oceania. 3. Varicella–zoster virus evolution and recombination The subfamily Alphaherpesvirinae, which contains the human herpesviruses VZV, HSV-1, HSV-2 and other mammalian and avian viruses, separated from other subfamilies of the family Herpesviridae 180–210 million years ago (McGeoch et al., 1995). The intranuclear replication and DNA replication machinery of alphaherpesviruses leads to an efficient proof-reading activity with a low rate of nucleotide substitution. The rate of synonymous nucleotide substitutions was demonstrated to be 3  108 substitutions per site per year (Sakaoka et al., 1994) and, therefore, much higher when compared to mammalian genomes but lower when compared to most RNA viruses. The out-of-Africa model for VZV evolution suggests that VZV coevolves with humankind and diversified from ancestral African VZV clades into Asian (clade 2) and European (clades 1 and 3) clades (Wagenaar et al., 2003; Peters et al., 2006). Another model suggests that VZV evolution is driven by climatic factors and that VZV clade distribution is associated with temperate and tropical climate conditions (Loparev et al., 2004). However, the data presented here (Table 1) suggest a geographic clustering of VZV clades rather than a clustering of VZV clades according to climatic factors. Moreover, it was suggested that recombination events may have influenced the evolution of the different VZV clades (Norberg et al., 2006; Peters et al., 2006; Schmidt-Chanasit et al., 2008b; McGeoch, 2009). Recombination between nucleotide sequences is a major process influencing the evolution of most species on Earth. Two different types of recombination mechanisms have been described in the family Herpesviridae: illegitimate and homologous recombination (Umene and Sakaoka, 1999). Homologous recombination is based on a reciprocal exchange in which a pair of homologous DNA sequences breaks and rejoins in a cross-over whereas illegitimate recombination occurs despite the absence of sequence homology (Leach, 1996). Both recombination mechanisms are coupled with viral DNA replication and may require cell factors (Thiry et al., 2005).

The importance of considering recombination in VZV evolutionary studies is underlined by the bewildering array of currently available methods and software tools for analyzing and characterizing it in various classes of VZV nucleotide sequence datasets (Norberg et al., 2006; Peters et al., 2006; McGeoch, 2009). Based on the analysis of 18 complete VZV genome sequences, it was suggested that clade 4 strains evolved through recombination of clade 1 with clade 2 strains (Peters et al., 2006). It was demonstrated that clade 4 strains showed a considerably similarity with clade 2 strains but that in ORFs 14–17 and ORFs 22–26 a greater similarity with clade 1 strains can be found. In line, BootScan analysis supported these findings (Peters et al., 2006). However, clade 5 strains were not included in the recombination analyses. Another group suggested that clades 4 and 5 strains evolved through recombination of clade 1 with clade 2 strains (Norberg et al., 2006). Fragmentation analysis revealed 15 and 14 distinct segments of interest for further evaluation of the DR strain and CA123 strain, respectively (Norberg et al., 2006). Subsequent phylogenetic analysis revealed that 11 segments clustered DR (clade 4) with pOka (clade 2) and four segments clustered DR with clade 1 strains. Similarly, 10 segments clustered CA123 (clade 5) with pOka (clade 2) and four segments clustered CA123 with clade 1 strains. In contrast to Peters et al. (2006), the areas of recombination were uniformly distributed throughout the whole genome. However, the analysis by Norberg et al. (2006) was only based on seven complete VZV genome sequences and clade 3 strains were not included in the analysis. A very recently published analysis suggested that clade 1 strains were derived from a recombinant of clades 3 and 4 strains (McGeoch, 2009). This study identified the different VZV clades by the examination of SNP patterns derived from whole genome sequences of all major VZV clades (clades 1–5) including 18 different strains. Using this approach, it was shown that clades 3 and 4 strains are almost completely composed of distinct alleles and contain little or no admixture from recombination with other clades. The alleles of clade 1 strains match those of the clade 3 strains for the most part but there are also sections that match with the clade 4 strains (McGeoch, 2009). Moreover, phylogenetic analysis using a Bayesian approach demonstrated that the recombinational genesis of clade 1 strains evidently took place later than most of the substitutional divergence events of the clades 3 and 4 strains and that clades 2 and 5 possess unique lineages of substantial relative depth, while the inferred existence of cross-over events obscures details of their deeper connections (McGeoch, 2009). The same set of 18 VZV full-genome sequences was analyzed in the current review using the recombination detection program version 3

[(Fig._3)TD$IG]

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more VZV full-genome sequences of strains belonging to clades 2 and 5. 4. Molecular studies of the Oka vaccine

Fig. 3. Recombination analysis based on 18 VZV full-genome sequences by CHIMAERA (A), MAXCHI (B) and RDP (C) methods implemented in the RDP3 program (Martin et al., 2005) demonstrated that clade 1 strains were derived from a recombinant of clades 3 and 4 strains with a clade 3 strain as major parent and a clade 4 strain as minor parent.

(RDP3) (Martin et al., 2005). Our analysis confirmed the results of McGeoch (2009) and demonstrated the beginning of the recombinant region at nt position 13,639 and the ending at nt position 35,698 (numbering according to the nt position of the clade 1 reference strain Dumas, GenBank accession number NC001348) (Fig. 3). The recombination event was confirmed by seven different methods (RDP, GENECONV, BootScan, MaxChi, Chimaera, SiScan and 3Seq) that are implemented in the RDP3 program and the associated average P-values are shown in Table 2. For a more refined recombination analysis it will be very important to include Table 2 Confirmation table demonstrating the average P-values of the methods used to detect recombination events between the five different VZV clades. Methods

Average P-value

RDP GENECONV BootScan MaxChi Chimaera SiScan 3Seq

0.006 0.29 0.014 0.00025 0.004 0.0000002 0.035

After a safe and effective live-attenuated varicella vaccine was originally developed in the early 1970s in Japan by Takahashi et al. (1974), the vaccine has been licensed for common use in the United States (US) since 1995 (Gershon, 2001). In 1998, the World Health Organization (WHO) recommended that routine childhood varicella vaccination should be considered in countries where the disease is an important public health and socioeconomic problem, where the vaccine is affordable, and where high and sustained vaccine coverage can be achieved (World Health Organization, 1998). To 2009, the varicella vaccine was used in childhood immunization programs in Australia, Canada, Germany, Greece, Qatar, South Korea, Saudi Arabia, Taiwan, USA, Uruguay, Italy, and Spain (Bonanni et al., 2009). All of the currently available varicella vaccines derive from a Japanese wild-type strain isolated from a child with typical varicella named Oka (pOka). Whereas pOka is thought to be virulent in vivo, the Oka vaccine virus (vOka) is attenuated. All vaccines distributed commercially have been reported to differ in passage of virus used and in stabilizers as well as other components of the vehicle (Gershon, 1997). The Varilrix1 vaccine (GlaxoSmithKline, Uxbridge, UK) underwent five episodes of terminal dilution resulting in alterations of vaccine SNP frequencies (D’Hondt et al., 1985). Furthermore, the Varivax1 (Merck Frossst, Quebec, Canada; Aventis Pasteur MSD, Leimen, Germany) and Varilrix1 vaccines have both been shown to display substantial differences from the Biken vaccine (Biken, Osaka, Japan) in terms of the frequency of vaccineassociated SNPs reported by Gomi et al. (2002). In addition, the Varilrix1 vaccine was shown not only to differ in vaccine marker profile from the Biken vaccine, but between two different lots separated in time by a single production year (Sauerbrei et al., 2004). Oka vaccine virus is known to provide 70–90% protection from any varicella and over 95% protection from moderate to severe disease (Gershon, 2001). Vaccinated persons can develop mild varicella termed as breakthrough. The disease occurs more than 42 days after varicella vaccination and represents wild virus infection. Most breakthrough diseases are very mild, the infectivity is relatively low and there is a low or no risk for complications (Va´zquez and Shapiro, 2005). Furthermore, vOka is able to establish latent infection in sensory nerve ganglia, and subsequent zoster has been demonstrated as a rare adverse consequence among vaccinees (Liang et al., 1998; Levin et al., 2003; Sharrar et al., 2001; Uebe et al., 2002). Phenotypic characterization revealed that vOka is temperature sensitive, exhibiting better growth at 34 8C compared to 39 8C, and replicates better in guinea pig fibroblasts than in human embryonic fibroblasts (Takahashi, 1996). Like wild-type VZV, vOka can infect both neurons and glial cells and can spread efficiently from cell-to-cell as demonstrated in the SCID-hu mouse model (Baiker et al., 2004). However, the ability to spread from Tcells to epithelial cells and the mean titers obtained from epithelial cell implants were reduced markedly (Moffat et al., 1998; Soong et al., 2000). Molecular biological studies have shown that there are characteristic SNPs in the ORFs 38, 54 and 62 of vOka, whose analysis provides reliable differentiation of wild-type viruses including pOka from vOka (LaRussa et al., 1992; Loparev et al., 2000; Sauerbrei et al., 2003). The comparison of complete DNA sequences of the Japanese varicella vaccine Biken manufactured by the Research Foundation for Microbial Diseases of Osaka University and its parental virus pOka revealed several genomic differences (Gomi et al., 2002). Altogether, 42 base differences in the 50 non-coding region as well as in the ORF 1, 3/4, 6, 9A, 10, 14, 18, 21, 22, 31, 35, 39, 45, 47, 50, 51, 52, 54, 55, 59, 61/62, 62, 62/63

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Table 3 Amino acid substitutions found by full-genome sequencing of vaccine Oka (vOka) and parental Oka (pOka) strains (Gomi et al., 2002). Open reading frame

Position

6 9 10 21 31 39 50 52 55 55 59 62 62 62 62 62 62 62 62 64

5745 10,900 12,779 31,732 58,595 71,252 87,396 90,535 97,748 97,796 101,089 105,310 105,356 105,544 106,262 107,252 107,599 107,797 108,838 111,650

Base substitution

Amino acid substitution

vOka

pOka

vOka

pOka

G T/C T/C T/C A/G T/C T/C A/G G/A T/C A/G A/G C G C C A/G A/G A/G A/G

A T T C A T T A G T A A T A T T A A A A

Pro Trp/Arg Ala/Val Thr/Ile Ile/Val Met/Thr Ser/Gly Ile/Val Ala/Thr Cys/Arg Leu/Pro Leu/Ser Val Ala Gly Gly Val/Ala Leu/Pro Met/Thr Gln/Arg

Ser Trp Ala Thr Ile Met Ser Ile Ala Cys Leu Leu Ile Val Arg Ser Val Leu Met Gln

and 64, resulting in 20 amino acid conversions (Table 3), could be detected. In addition, there are length differences in the tandem repeat regions R1, R2, R4 and in an origin of DNA replication. Fifteen of the described base substitutions, leading to eight amino acid substitutions, were found in the immediate early (IE) gene 62 region alone, which has been assumed to be responsible for attenuation of vOka (Argaw et al., 2000; Gomi et al., 2000, 2001). Noteworthy, the vOka preparation is composed of a mixture of genotypically distinct Oka strains. Sequencing results revealed a mixture of both vaccine virus and wild-type virus nucleotides (Gomi et al., 2002) also demonstrated in Varivax1 and Varilrix1 isolates (Sauerbrei et al., 2006). Gomi et al. (2000) demonstrated the presence of at least nine viral variants in the Biken vaccine by sequencing of subcloned fragments from VZV gene 62. In addition, Takayama and Takayama (2004) verified by plaque cloning that the Oka vaccine virus is composed of a mixture of at least six different clones. Although it is little evidence of varicella vaccine causing serious adverse consequences (Breuer, 2003), it has been speculated that individual strains in the varicella vaccine have pathogenic potential resulting in vaccine-related adverse events. Data indicate that a large number of variants can be associated with postvaccination rash or zoster caused by varicella vaccine (Loparev et al., 2007c; Quinlivan et al., 2004). However, there is currently no evidence that any vaccine-associated SNP is associated with heightened pathogenicity. On the contrary, the observations thus far suggest a random emergence of strains during the reactivation of the vaccine virus. The majority of the non-synonymous vaccine mutations occur in the ORF 62 encoding the IE62 protein that is likely to exert an important regulatory function in VZV replication since it is capable to transactivate viral genes and to increase viral DNA infectivity (Moriuchi et al., 1994). Accordingly, studies demonstrated that the in vitro transactivating capability of the vOka IE62 protein was reduced significantly compared to the parental IE62 protein (Gomi et al., 2001). Recent findings support the possibility that both viral replication and cell-to-cell spread may be diminished in vOka due to the altered potency of IE62 for inducing VZV gene transcription (Gomi et al., 2008; Yamanishi, 2008). In rashes due to the VZV vaccine, Quinlivan et al. (2004) reported only two conserved non-synonymous vaccine mutations in IE62 at positions 106,262 and 107,252, but Loparev et al. (2007c) observed two additional stable SNPs at positions 105,705 and 108,111 in a similar study. The SNP at the locus 107,252 has

also been described in a VZV clade 3 strain isolated from a patient with thoracic zoster after bone marrow transplantation (Sauerbrei et al., 2009). This can be the result of spontaneous mutation or might be emerged as result of recombination between clade 3 virus and vOka strain. The resulting amino acid substitution in position 628 is situated close to the main DNA-binding domain of the IE62 protein (Tyler and Everett, 1993). Interestingly, Lopez et al. (2008) reported the vaccine mutation at position 107,252 in a clade 5 strain causing an outbreak in a residential care home in the USA. These results suggest that this mutation is not responsible for conferring attenuation on the vaccine virus. Apart from these findings, investigations on the ability of IE62 derived from both pOka and vOka to transactivate selected VZV gene promoters indicate that mutations in vOka IE62 alone are unlikely to account for vaccine virus attenuation (Cohrs et al., 2006). Significant genomic changes of ORF 14 and 47, which can be responsible for the reduced ability of vOka to spread from T-cells to epithelial cells and the diminished replication in epithelial cell (Gomi et al., 2002; Soong et al., 2000), was detected. Furthermore, a study using chimeric vOka/pOka viruses suggested that mutations in ORF 30–54 are required for the attenuation of VZV vaccine (Zerboni et al., 2005). 5. Vaccine impact, recombination and recent changes in genotype distribution After implementation of varicella vaccination in many countries, it has to be expected that a substantial number of infants may carry the live-attenuated vaccine virus, which is also capable to induce latent infection and can reactivate to cause zoster (Uebe et al., 2002). Thus, vOka strains (clade 2) may be introduced in geographic regions, where other clades are predominant (LaRussa et al., 1997). In addition, re-infections with VZV wild-type strains may occur among vaccinated individuals (Hambleton et al., 2008) suggesting that recombination between wild-type VZV strains and vOka seems to be possible in vaccine recipients. Therefore, molecular surveillance of VZV genotypes is indicated and was performed by several national institutions such as in Australia, France, Germany, UK, and USA (Breuer et al., 2010). The new common nomenclature established recently will be useful for the interchange and comparison of genotyping data. To date, there is no evidence that implicates varicella vaccination in any of the observed shifts in VZV clade distribution.

8

[(Fig._4)TD$IG]

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Although alphaherpesviruses have been recognized as stable genetically having a low rate of nucleotide substitutions (McGeoch and Cook, 1994; Barrett-Muir et al., 2002; Tyler et al., 2007), recombination is thought to have played a crucial role in the evolution of VZV (Norberg et al., 2006; Peters et al., 2006; McGeoch, 2009). To date VZV wild-type recombinants have been rarely reported (Quinlivan et al., 2002; Barrett-Muir et al., 2003; Sengupta et al., 2007). Detected recombination events are ancient and shared by complete clades of circulating strains. However, if recombination can occur between wild-type isolates, recombination might occur presumably also between wild-type and vaccine strains. Thus, it has been documented in several studies that genetic alterations of VZV may be created both in vitro (Dohner et al., 1988) and in vivo (Shiraki et al., 1991) by recombination between vaccine and wild-type viruses. Furthermore, in vivo recombination between two different vaccine viruses has been described using the example of pseudorabies virus, a porcine alphaherpesvirus (Dangler et al., 1993). One of the most important requirements for viral recombination in vivo, the co-infection of a single person with strains belonging to two different clades, has been proven in a case of varicella (Quinlivan et al., 2009). Most recently, Breuer et al. (2010) referred to the emergence of new wild-type/vaccine recombinant viruses, which were sequenced partially. Two of them are vaccine-clade 1 and one is vaccine-clade 3. After sequencing by the scattered SNP method, a putative clade 2/clade 1 recombinant has been reported by Sengupta et al. (2007) and Sauerbrei et al. (2008) described a potential clade 3/ clade 2 recombinant strain, that has to be differentiated from the provisional clade IV using full-genome sequencing. All these findings suggest that further wild-type vaccine recombinant viruses have to be expected. Thus, monitoring of VZV genotypes for the emergence of recombinant strains should include full-genome sequencing, which is the preferred method to analyze recombinant viruses. To date, most genotyping data are based on the analysis of only a few loci in the VZV genome and only 23 complete genome sequences have been reported (Breuer et al., 2010). Therefore, it seems to be possible that the frequency of recombinant viruses has been underestimated in the past and will increase in coming decades. Another reason for the low frequency of circulating VZV recombinant strains detected so far may be the relatively stable geographic separation of viral strains attributed to the different clades (Barrett-Muir et al., 2002; Loparev et al., 2004; Inoue et al., 2010). However, recent data support the hypothesis that the separation of VZV clades does not only take place strictly according to geographic points of view. Several other factors such as the level of immigration, the travel behavior of inhabitants and clade-specific properties may be of significance. Sengupta et al. (2007) analyzed the VZV genotypes in patients from East London with zoster. On the one hand, the results demonstrated that strains of the clades 1 and 3 were most commonly found, representing 58% and 21% of all isolates, respectively. Their prevalence has been relatively stable over time. On the other hand, an increase in the proportions of clades 5 and 2 strains has occurred and was explained with the higher rates of immigration. In the Thuringia region of Germany, a higher genetic diversity of clinical VZV isolates from patients with varicella compared to patients with zoster was demonstrated recently (Sauerbrei and Wutzler, 2007b; Sauerbrei et al., 2008). While in zoster patients, only strains of the clades 1 and 3 could be detected, VZV clades 1, 3 and 5 were found in nearly equal incidence in isolates from patients with varicella. These findings suggest a changing prevalence of VZV strains belonging to different clades, possibly due to the recent import of clade 5 strains by African immigrants. Most recent data collected by the analysis of 200 VZV strains from patients with varicella and 100 strains from patients with zoster revealed that in varicella patients 46% of all strains clustered into clade 3, 30% into clade 1, 21% into clade 5 and 1% into clade 2

Fig. 4. Distribution of VZV clades in 200 patients with varicella and 100 patients with zoster. Samples were collected between 2003 and 2009 in the German federal state Thuringia. Fragments of the open reading frames (ORF) 1, 21, 22, 37, 50, 54, and 60 were analyzed by sequencing. In addition, polymorphisms of PstI (ORF 38), BglI (ORF 54) and SmaI (ORF 62) were characterized.

(vOka). In zoster patients, 51% of all strains were attributed to clade 3, 47% to clade 1 and 1% of each to clade 2 (vOka) and clade 4 (Fig. 4). These results confirm a considerable prevalence of clade 5 strains exclusively in varicella patients of the German region Thuringia although the proportion of African immigrants is low. The uniform ORF 62 pattern of clade 5 strains (Sauerbrei et al., 2009) gives evidence that these strains were introduced via few sources from African countries. Therefore, clade 5 might have the potency to spread more effectively in the population than the European clades. Furthermore, the current findings from Germany demonstrate that the clade 3 is the most frequent genotype in both varicella and zoster patients. This is in line with findings from Iceland and Finland (Loparev et al., 2009), but in contrast to the most other European countries such as UK (Sengupta et al., 2007). Finally, the introduction of varicella vaccination has led to the detection of clade 2 strains that can be characterized as vOka strains without exception. 6. Conclusion and remarks The data summarized in this review allowed to analyze the distribution and evolutionary history of several VZV clades in more detail. In early genotyping studies, VZV DNA was mainly characterized using RFLP analysis which demonstrated interstrain variations among wild-type isolates as well as differences between wild- and vaccine-type viruses. Attempts to improve genotyping methods employed DNA sequencing to screen for SNP in different selected ORFs of the VZV genome (Barrett-Muir et al., 2003; Faga et al., 2001; Loparev et al., 2004), but there was no consensus for the nomenclature of VZV strains. With the beginning of the 21st century and the introduction of routine varicella vaccination programs, there was a significant rise in the number of available VZV full-genome sequences (Grose et al., 2004; Norberg et al., 2006; Peters et al., 2006) which are essential for the definition of different VZV clades. To date, 23 VZV full-genome sequences are available and phylogenetic analysis of these VZV full-genome sequences demonstrated the presence of at least five different VZV clades that have been classified using a novel universal VZV nomenclature (Breuer et al., 2010). In addition, there were defined two provisional VZV clades VI and VII to be confirmed by full-genome sequencing. Thus, this common classification of VZV clades allows the world-wide interchange and comparison of

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VZV genotyping data for the first time. However, there is an urgent need to sequence more complete VZV genomes, especially from clades 2 and 5 strains and from the provisional clades VI and VII strains for a more refined analysis of the deep relationships between the clades. To date, only SNP-based studies of selected VZV genome targets allowed the typing of appropriate numbers of VZV strains for molecular epidemiological studies (Faga et al., 2001; Loparev et al., 2004, 2009; Quinlivan et al., 2002; Wagenaar et al., 2003). On the basis of these studies, the occurrence of novel clades cannot be ruled out. Clades 1 and 3 strains have been detected mainly in Europe, the Americas and Oceania, whereas clade 2 strains are dominant in Asia and clade 5 strains are dominant in Africa. There is a relatively large amount of molecular epidemiological data from European and American countries. Data from Germany show a changing scene of VZV clades in varicella and zoster over time, probably caused by the importation of clade 5 strains. In the future, it will be important to analyze more VZV strains from areas or continents with so far very limited information regarding the circulating VZV clades, i.e. Africa, Asia and Arabia. Recombination analysis of VZV full-genome sequences suggested also the presence of recombinant VZV strains (Norberg et al., 2006; Peters et al., 2006; McGeoch, 2009). Recent findings indicate that the frequency of recombinant viruses has been probably underestimated by the use of only a few loci in the VZV genome for genotyping. In particular, the possibility of recombination between wild-type and vaccine strains should be considered after entering of varicella vaccine strains, clustering into clade 2, into the population of countries where the routine varicella vaccination has been introduced. Thus, even though the advantages of the varicella vaccination are beyond debate, recent data suggest that molecular surveillance of VZV genotypes is indicated in more national institutions than in Australia, France, Germany, UK, and US (Breuer et al., 2010). Conflict of interest The authors do not have commercial or other associations that might pose a conflict of interest (e.g., pharmaceutical stock ownership or consultancy). Ethical statement No human subjects or animals were used in this study. References Argaw, T., Cohen, J.I., Klutch, M., Lekstrom, K., Yoshikawa, T., Asano, Y., Krause, P.R., 2000. Nucleotide sequences that distinguish Oka vaccine from parental Oka and other varicella zoster isolates. J. Infect. Dis. 181, 1153–1157. Arvin, A.M., Moffat, J.F., Redman, R., 1996. Varicella–zoster virus: aspects of pathogenesis and host response to natural infection and varicella vaccine. Adv. Virus Res. 46, 263–309. Arvin, A.M., 1999. Chickenpox (varicella). In: Wolff, M.H., Schu¨nemann, S., Schmidt, A. (Eds.), Varicella–Zoster Virus. Molecular Biology, Pathogenesis, and Clinical Aspects. Karger, Basel. Contrib. Microbiol. 3, 96–110. Baiker, A., Fabel, K., Cozzio, A., Zerboni, L., Fabel, K., Sommer, M., Uchida, N., He, D., Weissman, I., Arvin, A.M., 2004. Varicella–zoster virus infection of human neural cells in vivo. Proc. Natl. Acad. Sci. U.S.A. 101, 10792–10797. Barrett-Muir, W., Nichols, R., Breuer, J., 2002. Phylogenetic analysis of varicella– zoster virus: evidence variation of varicella–zoster virus: evidence of intercontinental spread of genotypes and recombination. J. Virol. 76, 1971–1979. Barrett-Muir, W., Scott, F.T., Aaby, P., John, J., Matondo, P., Chaudhry, Q.L., Siqueira, M., Poulsen, A., Yamanishi, K., Breuer, J., 2003. Genetic variation of varicella– zoster virus: evidence for geographical separation of strains. J. Med. Virol. 70, S42–S47. Bonanni, P., Breuer, J., Gershon, A., Gershon, M., Hryniewicz, W., Papaevangelou, V., Rentier, B., Ru¨mke, H., Sadzot-Delvaux, C., Senterre, J., Weil-Oliver, C., Wutzler, P., 2009. Varicella vaccination in Europe—taking the practical approach. BMC Med. 7, 26. Breuer, J., 2003. Monitoring virus strains variations following infection with VZV: is there a need and what are the implications of introducing the Oka vaccine? Commun. Dis. Publ. Health 6, 59–62.

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