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Journal of Virology, February 2002, p. 1971-1979, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1971-1979.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Phylogenetic Analysis of Varicella-Zoster Virus: Evidence of Intercontinental Spread of Genotypes and Recombination

Winsome Barrett Muir, Richard Nichols, and Judith Breuer^*

Schools of Medicine and Biological Sciences, Queen Mary College, University of London, London E1 1BB, England

Received 13 September 2001/ Accepted 12 November 2001

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A heteroduplex mobility assay was used to identify variants of varicella-zoster virus circulating in the United Kingdom and elsewhere. Within the United Kingdom, 58 segregating sites were found out of the 23,266 examined (0.25%), and nucleotide diversity was estimated to be 0.00063. These are an order of magnitude smaller than comparable estimates from herpes simplex virus type 1. Sixteen substitutions were nonsynonymous, the majority of which were clustered within surface-expressed proteins. Extensive genetic correlation between widely spaced sites indicated that recombination has been rare. Phylogenetic analysis of varicella-zoster viruses from four continents distinguished at least three major genetic clades. Most geographical regions contained only one of these three strains, apart from the United Kingdom and Brazil, where two or more strains were found. There was minimal genetic differentiation (one or fewer substitutions in 1,895 bases surveyed) between the samples collected from Africa (Guinea Bissau, Zambia) and the Indian subcontinent (Bangladesh, South India), suggesting recent rapid spread and/or low mutation rates. The geographic pattern of strain distribution would favor a major influence of the former. The genetic uniformity of most virus populations makes recombination difficult to detect. However, at least one probable recombinant between two of the major strains was found among the samples originating from Brazil, where mixtures of genotypes co-occur.

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Genetic variation among strains of human herpesviruses has been used to distinguish viral genotypes and to conduct epidemiological studies (7, 14, 33, 40, 45-51). Variation results predominantly from single nucleotide polymorphisms (SNPs) or from alteration in the composition and number of repeat elements present either within the internal and terminal repeat regions or within tandem direct reiterations scattered throughout the genome (7, 8, 27, 35). Genetic variation in varicella-zoster virus (VZV) has been defined by the presence or absence of restriction sites, such as a PstI site in gene 38 (25) and a BglI site in gene 54 (1), or differences in the number of repeat elements within the five repeat regions in the VZV genome (5, 20, 24, 25, 26, 28, 43, 44). These methods were found to distinguish viruses from different geographic regions and have been used to differentiate between the live attenuated Japanese Oka vaccine strain and wild-type viruses circulating in the United States and United Kingdom (17, 21, 23, 29, 47). Distinctive restriction enzyme patterns have also allowed differentiation between epidemiologically unrelated viruses, while viruses occurring in a single outbreak have been shown to be identical (20, 41). The establishment of latency by the virus in the dorsal root ganglion does not appear to affect the genotype, as evidenced by the identical restriction enzyme profiles of the infecting and reactivating strain from a single individual (42). Restriction enzyme profiles have also been shown to remain stable on serial passage in tissue culture (20).

Using these established methods, we have previously shown a mixture of genetically distinct strains to be circulating in the United Kingdom, most particularly in the East End of London, where the proportion of VZV strains carrying the BglI restriction endonuclease site in gene 38 increased from 10% in the early 1980s to more than 30% in the 1990s (22). Sampling of viruses from outside the United Kingdom showed a 90 to 100% prevalence of BglI-positive viruses in Asian and African countries, while the United States was similar to the United Kingdom (4). More recently several groups, including ours, have identified additional SNPs which can be used to genotype VZV strains (3, 12; V. N. Loparev and D. S. Schmid, Abstr. 26th Int. Herpesvirus Workshop, abstr. 3.15., 2001). Using the SNP map we have generated, estimates of VZV variation have been derived. In this report we use phylogenetic and population genetic analysis, which has enabled us, for the first time, to examine the evolutionary relationships between genotypes and to analyze the putative mechanisms by which VZV evolution and spread are likely to occur in the future.

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Samples. The polymorphic map was developed using 10 VZV isolates randomly selected from around the United Kingdom. These data were used to estimate the time since the common ancestor of the major clades (see below). This calculation does not require a large sample size, because of the redundancy of information from similar sequences of the same clade, but it does benefit from the extensive sequence survey. The most informative sites were selected for further analysis (Fig. 1). We proceededto test further 10 United Kingdom samples for the whole set of primers to verify this choice and to establish that these were SNPs and not rare variants or PCR/sequencing artifacts. A larger sample, made up by an additional 67 strains typed at the phylogenetically informative loci, was used to survey the global distribution of genetic diversity. These comprised an additional 25 United Kingdom samples, collected from patients with varicella and zoster in East London, and 42 non-United Kingdom samples (Fig. 1).

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FIG. 1. Alignment of nucleotide polymorphisms in strains of VZV from around the world. The country of origin of the virus is shown in the first column (Netherlnd, The Netherlands; G. Bissau, Guinea Bissau; B'desh, Bangladesh; S. India, South India; UK, United Kingdom). The regions which contained SNPs among the original 10 United Kingdom viruses typed are shown. Shaded boxes represent ORFs in which nucleotide changes were nonsynonymous. Regions within ORFs 1, 21, 50, and 54 which show fixed differences between genotypes were used to type additional strains from the United Kingdom and around the world; indicates recombinant virus. Letters A, B, and C refer to different genotypes as defined by phylogenetic analysis (see Fig. 2). Virus originating in the United Kingdom (blue), Brazil (brown), Zambia or Guinea Bissau (orange), South India or Bangladesh (yellow), and Japan (magenta) are shown.

DNA extraction and amplification. DNA was extracted from 200 µl of each vesicle fluid sample using the QIAamp Blood Mini Kit (Qiagen Ltd., Crawley, United Kingdom). Viral DNA from each sample was initially genotyped at four loci by methods previously established (3). The 56 sets of primers shown in Table 1 were designed to amplify 500-bp regions at 3,000-bp intervals (3). DNA amplification reactions were performed in 100-µl reaction volumes using 1 U of AmpliTaq Gold DNA polymerase enzyme (Perkin-Elmer). The mixture comprised PCR buffer II (Perkin-Elmer), 200 µM concentrations of each deoxynucleotide triphosphate, each primer at a concentration of 0.2 µM, 1 µl of test or control DNA extract, and an optimal MgCl₂ concentration. The optimum magnesium concentration was determined for each primer pair by titration from 1 to 4 mM MgCl₂ using the positive control DNA extract (3). Thermal cycling included an initial hot start at 95°C for 12 min, followed by 30 to 40 cycles of 94°C for 1 min, the annealing temperature for 1 min, and then 72°C for 1 min, with a final extension at 72°C for 10 min. PCR products were visualized by gel electrophoresis in agarose containing ethidium bromide, alongside a 100-bp ladder (Gibco BRL).

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TABLE 1. Primers used to amplify and sequence viruses

HMA. The heteroduplex mobility assay (HMA) was optimized using PCR products spanning a BglI site in gene 54 from samples with and without the restriction site polymorphism. The method used has been previously described (3). Briefly, 2 µl of each PCR product was mixed with 2 µl of gel loading buffer and denatured by heating at 98°C for 5 min, followed by 68°C for 30 min, and then held at 4°C. The samples were then mixed with 7.5 µl of gel loading buffer (45% formamide, 30% ethylene glycol, 10 mM EDTA, 5% Ficoll, and 0.05% bromophenol blue and xylene cyanol). Samples were electrophoresed on a 6% polyacrylamide gel, with 0.6 g of piperazine/liter in Tris-taurine-EDTA (TTE) buffer containing 10% ethanediol and 13.75% formamide. After electrophoresis, the gel was fixed and stained by immersing it sequentially in 0.1% silver nitrate for 15 min, followed by 1.5% sodium hydroxide-0.3% formaldehyde solution for approximately 5 min until bands were just visible. The gel was fixed in 5 to 6% glacial acetic acid for 5 min and removed from the silane-coated glass plates by immersion in 1.5% sodium hydroxide for 20 min.

DNA sequencing. Polymorphisms identified by HMA were confirmed and characterized by nucleotide sequencing of PCR products using the relevant PCR primers in an ABI Prism dRhodamine terminator cycle sequencing reaction mix (Perkin-Elmer Applied Biosystems) according to the manufacturer's instructions. Cycle sequencing reactions were electrophoresed on an ABI 377 Analyser (Applied Biosystems Inc.). Sequences generated were analyzed using Sequence Navigator (Applied Biosystems Inc.) and compared to that of the published VZV (strain Dumas) sequence (9, 11) in order to identify sequence polymorphisms.

Phylogenetic analysis. Aligned SNPs identified in 10 United Kingdom VZV strains were analyzed by the DNAPARS program within the Phyllip package (13), using the Dumas strain sequence as an outgroup (3). The primer pairs found to flank informative SNPs were used to analyze additional strains from the United Kingdom and other countries (Fig 1). The analysis was conducted using the PAUP 4.0b8 program. A neighbor-joining tree was calculated to illustrate the distribution of intergenotype differences. The support for the branching pattern was assessed by bootstrapping, using maximum parsimony as the criterion. Evidence of linkage disequilibrium was evaluated using Fisher's exact tests to compare the frequency of allelic combinations at pairs of loci with the frequencies expected under free recombination. The data were also used to calculate the nucleotide diversities within populations and between populations and the net difference between populations (_X, _XY, _A) using the methods of Nei (34).

Time since branching of the major clades. The estimate of the time since the splitting of the major clades depends on the mutation rate, µ. The maximum likelihood value for the time can be calculated from the number of substitutions (x = 12) using the Poisson likelihood function, L(x|µ,t) ^xe, where is the expected number of synonymous substitutions in b bases ( = µb2 t). Similarly the range of plausible values could be calculated as a likelihood curve. The synonymous substitutions and their rate were used, as this varies less between genes and taxa.

The 95% limits (the posterior 95% equiprobable interval) were calculated from this equation by using the mutation rate of µ = 1.0 x 10^-7 substitutions per nucleotide per year, obtained from a study of related alphaherpesviruses (31). The calculation assumed a uniform prior on the time (t). The distribution could therefore be obtained directly by numerical integration of the distribution for a range of mutation rates. These were normally distributed around this mean for µ, with a standard error of 20% to allow for uncertainty in the estimate and in extrapolation between viruses (but see Discussion).

Estimate of mutation rate. An alternative method of analysis is to assume that the major clades diversified at or before the major human migrations 100,000 years ago (100 kya), as has been suggested for alphaherpesviruses. An estimate of µ can be obtained by substituting rates in the likelihood function and examining the relative support for times exceeding 100 kya. We use the criterion that 5% of the distribution should exceed 100 ky (equivalent to a 5% probability under a uniform prior probability distribution).

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The HMA does not identify polymorphisms within the terminal 50 bases of the PCR product (15). Allowing for this, approximately 23,266 nucleotides (18.6% of the genome) were screened in 10 United Kingdom viruses. Fifty-eight polymorphic positions were identified (0.25%), and nucleotide () diversity was estimated to be 0.00063 (standard error, 0.00018). This agrees with previous estimates obtained by restriction fragment length polymorphism analysis (44). Sixteen of the nucleotide differences coded for an amino acid change (3), and the open reading frames (ORFs) in which they were located are shown in Fig. 1.

There were highly significant nonrandom associations (linkage disequilibrium) between alleles at widely separated loci. Of the 351 pairwise comparisons between loci, 73 showed associations that were significant at the 1% level. Under the null hypothesis of linkage equilibrium, only 3.51 comparisons would be expected to show this level of significance (Table 2). This result suggested that recombination had little effect on the evolution of the genotypes, and so phylogenetic methods were used to represent the relationships between the genotypes. The United Kingdom genotypes fell into three major clades (Fig. 2), designated A, B, and C.

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TABLE 2. Nucleotide diversities estimated from the four regions of 1.9 kb typed worldwidea

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FIG. 2. Phylogenetic tree of varicella-zoster virus strains by the neighbor-joining method. The countries from which specimens were obtained are shown: Bang, Bangladesh; Brasil, Brazil; Jap, Japan; GB, Guinea Bissau; Neth, The Netherlands; Sind, South India; ZAMB, Zambia. Bootstrap values separating clades A, B, and C are shown. + denotes additional viruses with identical sequence.

To map the worldwide distribution of genotypes, we used a subset of informative markers. Four regions, located in ORFs 1, 21, 50, and 54, which contained fixed differences between the major clades were selected manually and used to analyze a further 25 United Kingdom viruses (Fig. 1). This restricted marker set gave distinct genotypes, consistent with the previously identified clades. Genotyping additional informative markers located in ORFs 55, 20, and 47 did not reveal further genotypes (data not shown). Additional genotyping of 42 viruses from Africa, Asia, Europe, and South America (Fig. 1 and 2) using the four informative regions was therefore undertaken. Phylogenetic analysis of all of the viruses at the above four regions, representing 1,895 bp, is shown in Fig. 2. A bootstrap analysis using the maximum parsimony criterion was used to assess the support for the major clades. The number of inter- and intrapopulation nucleotide differences at these sites ranged from 0 to 13 and 1 to 12, respectively. These values were standardized as gross and net nucleotide diversities, using the methods set out by Nei (34), and are shown in Table 2.

The estimated time since the common ancestor of the major clades was 3,000 to 19,000 years, assuming the mutation rate derived from other alphaherpesviruses. The upper limit on the mutation rate that remains consistent with a divergence time of 100,000 years was one-seventh of the value for herpes simplex virus (HSV) type 1 and alphaherpesviruses (1.4 x 10^-8).

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Evolutionary inference from the phylogenetic data. Our estimate of genetic diversity of VZV is 0.00063, which is 10 times lower than that obtained for HSV and 40 times less than estimated for cytomegalovirus (CMV) (36, 51). This difference could be due to a lower mutation rate, a more recent common ancestry, or a combination of the two. Most striking is the genetic uniformity within and between samples from Guinea Bissau, Zambia, Bangladesh, and Southern India. In pairwise comparisons between genotypes from these localities, a maximum of one substitution was found in the 1.9 kb surveyed. Although small samples were obtained from each locality, the broad geographical scope precludes a sampling artifact. The human populations in these countries are not thought to have a particularly recent common ancestry (6), so the low differentiation of VZV indicates possible spread subsequent to the initial colonization of these areas. The contrasting higher level of diversity in the United Kingdom and Brazil may be explained by the history of recent human migration. There is clear evidence from the United Kingdom in support of the hypothesis of viral spread associated with migration. In East London, the frequency of clade A viruses among cases of varicella has increased with time, during a period when immigrants from the Indian and African subcontinents have come to make up more than 25% of the population (22). Clade A viruses are characterized by a BglI restriction site in gene 54 and are ubiquitous in Asia, Africa, and the Far East but generally make up fewer than 10% of British strains (22).

One way of interpreting the differentiation between populations is to make use of it to estimate the time of divergence. This estimate is conventionally obtained from the net accumulation of nucleotide diversity (_a) after subtracting an estimate of the diversity within the ancestral populations, which is obtained from the current diversity (34). Unfortunately, this calculation is not appropriate for VZV, as we have evidence that the high diversity of current populations may be a consequence of mixing, which has not yet reached equilibrium. We instead obtain an alternative estimate of the time (t) since the splitting of the major clades rather than populations, from the number of synonymous substitutions that have accumulated between them. This calculation requires an estimate of the mutation rate. One possible approach is to make use of estimates of mutation rates obtained from related viruses. For example, a synonymous mutation rate of 10^-7 (per year) has been obtained from differentiation between HSV type 1 strains from different parts of the world. It would imply that differentiation was initiated at the time of human dispersal out of Africa around 100 kya and is also consistent with rates estimated from other alphaherpesviruses (31, 32, 36). When this rate is applied to the VZV data, it leads to a much more recent estimate, implying that the currently circulating strains of VZV have spread in the past 3,000 to 19,000 years.

This interpretation is somewhat at odds with established estimates of varicella-zoster dispersal (19, 31, 32). Although the calculation allowed for some error on the estimate of the mutation rate (standard deviation, 20%), an alternative explanation is that the mutation rate of VZV is substantially lower than that of other alphaherpesviruses. Our calculations showed that if the rate were one-seventh of that of other alphaherpesviruses, then the different clades could date back 100,000 years. Is such a low rate plausible? Given the similar biology of the alphaherpesviruses, a lower mutation rate per division seems unlikely.

Is it then possible that VZV has a smaller number of divisions per year than other herpesviruses? The natural history of varicella is of primary infection in childhood following which the virus remains quiescent before reactivating once in adulthood, although recent evidence has confirmed observations that subclinical reactivation of VZV is not uncommon (30). The number of replication cycles before latency is established could be as low as 20 (19), and viral shedding is limited to the duration of lesions (approximately 5 to 7 days). By contrast, herpes simplex virus is known to have multiple reactivation episodes, which give rise to both symptomatic and asymptomatic viral shedding. Similarly CMV is 40 times more variable than VZV (51). This virus appears to be more distantly related to VZV than the alphaherpesviruses (32), but it is not sufficiently different that it is likely to be subject to a higher mutation rate per division. Instead, the same two explanations that we discussed for HSV may explain its higher diversity: a more ancient ancestry or a higher number of divisions since the common ancestor. The more ancient ancestry could be again explained by the mode of infection, which typically involves close contact. Furthermore, although CMV may be latent in mononuclear cells, there are long periods of asymptomatic shedding which suggest a high rate of division per unit time.

While the activity of VZV between varicella and zoster is not quantified, it is instructive to calculate the effect on the number of divisions per year under the assumption that this is an essentially quiescent period. The relevant transmission dynamics can be assessed using the parameters estimated by Schuette and Hethcote (39), which indicate that the majority of infections along any evolutionary lineage will be from varicella case to varicella case. The proportion of zoster episodes in the evolutionary history will be lower, first because of the lower relative infectivity (0.07) and second because only around 15% of cases reactivate as zoster. The latent period for varicella is only around 14 days, whereas the mean quiescent period before zoster activation is around 40 years. The ratio of time spent quiescent along an evolutionary lineage is given by (n_z vt_z p_z + n_v t_v p_z)/(n_z vt_z + n_v t_v), where n_z and n_v are the proportion of the population with zoster and varicella, respectively, t_z and t_v are the periods between initial infection and transmission, and p_z and p_v are the proportion of time spent quiescent between infection and transmission (p_z 1 and p_v 0). The infectivity of zoster (relative to varicella) is given by v. The values of n depend on the population demographics and viral epidemiology of the population, but we estimate that the proportion of time spent quiescent is of the order of 96%. HSV may spend less time quiescent, and since the infectivity and interval of each episode are relatively constant, the proportion of quiescent time along an evolutionary lineage will correspond to that within an individual. It is plausible that the proportion of time quiescent could be several times smaller than for VZV. Although this explanation of low diversity in VZV may be credible, the issue is most likely to be resolved by a more accurate calibration of the difference in mutation rate between VZV and other herpesviruses.

Although rapid spread and a low mutation rate could both explain the low level of genetic diversity of VZV, the geographical distribution and relatedness of strains does suggest that the spread of VZV subsequent to the major human migrations has made a strong contribution to its geographic epidemiology. The validity of this hypothesis is underlined by the recent spread in London of clade A strains, which appears to coincide with the major period of immigration from the Indian subcontinent and Africa to the United Kingdom. Such rapid spread is possible because VZV, uniquely among herpesviruses, is transmitted by aerosolization of virus, resulting in airborne epidemic infection. Geographic spread may be particularly rapid in warmer regions, where varicella occurs on average 10 years later in life (16). In this scenario, the disease is transmitted between individuals who are more mobile and who mix more freely than the children who account for the majority of infectious cases in more temperate climates.

Significant associations (linkage disequilibrium) between SNPs that are widely spaced within the genome suggest low recombination rates. Recombination rates, however, cannot be calculated from population genetic data because there is evidence of population subdivision, so that the different haplotypes may not come into contact. This study revealed that two geographic areas, London in the United Kingdom and Rio de Janeiro in Brazil, are populated with mixtures of strains. One haplotype originating with Brazil (Fig. 1) is most parsimoniously explained as a recombinant between A and C strains which coexist in the region. At least two other strains, UZ 42 and UZ 42+ (Fig. 1 and 2) from London, are also likely to be recombinants. Although in vitro recombination of the vaccine vOka strain with a wild-type U.S. strain has been described (10), this is the first evidence of recombination between strains occurring in vivo.

Recombination of wild-type strains may have consequences for virulence and selection. For example, the MSP VZV strain, in which a single nucleotide substitution results in an amino acid change from aspartate to asparagine in glycoprotein E, appears to be more virulent in the skin SCID-hu mouse model (37, 38). Epidemic spread of VZV affords the opportunity for repeated and widespread exposure of immune and naïve populations to circulating virus, and reinfection is well described (2, 18). In these circumstances, cocirculation of distinct wild-type genotypes, such as occurs in East London, will allow measurement of the rate of recombination and assessment of its contribution to VZV evolution. Such data may prove useful in understanding the spread and pathogenesis of VZV, especially against a background of mass immunization with the attenuated Oka vaccine.

 
This work was supported by grants from North Thames Health Authority Research & Development and the Special Trustees of St. Bartholomew's Hospital.

We thank colleagues who provided samples for this study, including Yamima Talukdar (Bangladesh), Marilda Siqueira (Brazil), Peter Aaby (Guinea Bissau), Koichi Yamanashi (Japan), Jacob John (South India), and Patrick Mtondo (Zambia).

 
* Corresponding author. Mailing address: Department of Medical Microbiology, 25-29 Ashfield St., London E1 1BB, England. Phone: 44 207 377 7141. Fax: 44 207 375 0518. E-mail: j.breuer{at}mds.qmw.ac.uk.

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Journal of Virology, February 2002, p. 1971-1979, Vol. 76, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.4.1971-1979.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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