Contrasting Geographic Distribution Profiles of the Herpes Simplex Virus Type 1 BgO _L and BgK _L Variants in Japan Suggest Dispersion and Replacement

Abstract

The lifelong latent infection-reactivation mode of infection of herpes simplex virus type 1 (HSV-1) transmitted by close contact has allowed a diversity of restriction fragment length polymorphism (RFLP) variations to accumulate in human populations. Whether and how the variants of the HSV-1 that is ubiquitous worldwide spread to different human populations is not clear. In our previous study the geographically gradient distribution of the HSV-1 BgK L variant, which is a good marker for the BgK L :SaCFJ M :SaGH M :SaD/E L :KpM S variant, suggested that BgK L dispersed geographically. Southern hybridization analyses showed that in BgK L the BglII cleavage site between the BglII K and small "Q/#13" fragments is lost, the SalI cleavage sites between the SalI J and C and between SalI F and J fragments are lost, and the SalI E fragment is abnormally large (SaE L variation). The RFLP and geographic distribution of one more HSV-1 RFLP variant, BgO L , were comparatively analyzed. The BglII cleavage site between the BglII O and Q/#13 fragments is lost in BgOL. BgO L clinical isolates were not associated with any of the SaCFJ M , SaE L , SaGH M , or KpM S variations, whereas one-fourth of the non-BgO L :non-BgK L isolates was associated with SaCFJ M and SaGH M , indicating that BgK L and BgO L are distant in terms of diversification. BgO L is distributed highly in the northeastern region and the southwestern island of Kyushu but is rare between the two regions in Japan, in a remarkable contrast to BgK L . These are the first epidemiologic data to show contrasting geographic distribution profiles of two HSV-1 variants and suggest the gradual dispersion and replacement of HSV-1 variants.Restriction enzyme fragment length polymorphism (RFLP) is useful and widely used to differentiate the herpes simplex virus type 1 (HSV-1) isolates and strains (11,17,27,(35)(36)(37). The data on genetic variability based on DNA sequencing of clinical HSV-1 isolates are limited compared to other human herpesviruses (4,5,8,22,23,41,50). The different clustering of RFLP profiles in the HSV-1 clinical isolates in several countries and/or continents has been documented (38, 39). Intriguingly, however, the recent report by P. Norberg et al. (25) indicates that there are HSV-1 genotypic groups in HSV-1 clinical isolates from Caucasian individuals in a geographically restricted area (the western part of Sweden). HSV-1 is ubiquitous worldwide and is transmitted by human close contact (2, 47). It is not known whether and how HSV-1 variants have been replaced or are replaceable by other HSV-1 variants in human populations or geographic regions. The base sequence diversity of HSV-1 is explained by the evidence that HSV-1 diverged from HSV-2 approximately 8.4 millions years ago (19). Thus, HSV-1 arose earlier than modern humans (18, 24), cospeciated with the human host (19), and persisted in accumulating nonlethal HSV-1 variants and mutants because of the latency and reactivation mode of HSV-1 infection. HSV-1 establishes a latent infection in the gan...

The Herpes Simplex Virus Type 1 BgKLVariant, Unlike the BgOLVariant, Shows a Higher Association with Orolabial Infection than with Infections at Other Sites, Supporting the Variant-Dispersion-Replacement Hypothesis

“…The loss of the BglII cleavage site between the BglII K (genomic residues 14588 to 25147, 10,560 bp, strain 17) and Q/#13 (genomic residues 25148 to 25378, 231 bp, strain 17) fragments (8,21) indicates a mutation at or adjacent to residues 25147 to 25148 in the coding region of the U L 12 gene (genomic residues 25007 to 26887, strain 17, DNase/alkaline nuclease) (26,31), as summarized in Table 2. The loss of the SalI cleavage sites between the SalI C and J fragments and between the SalI F and J fragments, resulting in SaCFJ M (8,21), indicates a mutation in the repeated sequence "b" and its inverted sequence "bЈ" (30) (at or adjacent to genomic residues 5462 to 5463 and 12904 to 120905, respectively, in strain 17 DNA) ( Table 2). This mutation may affect the gene for R L 2 (residues 2261 to 5489 and residues 120882 to 124110, strain 17, ␣0 or ICP0 protein) and latency-associated transcript (LAT) genes (residues 118802 to 127143) (NCBI gene identification 2828259) (9,31,34,46).…”

“…The laboratory strain HF was described previously (43)(44)(45). HSV-1 from virus stocks that had been prepared shortly after isolation were propagated on Vero cells (36,41,42,45) (8,21), with the high, low, and lower RFs of BgK L or BgO L being categorized. The level of significance was a P value of Ͻ0.05 (two tailed).…”

“…The geographic distribution of BgK L forms a gradient, suggesting that it dispersed from Shikoku Island to the surrounding regions of Japan (21). Furthermore, the contrasting geographic distribution of BgK L and BgO L variants suggests that the former may have displaced the latter (8).…”

“…Almost all BgK L variant isolates possess the three different SalI RFLP variations designated SaCFJ M, SaE L , and SaGH M , as well as the KpnI RFLP variation KpM S (8,21). Thus, the BglII K L variation is a surrogate RFLP marker for the five highly associated mutations (21).…”

“…We took this approach because the very large size of the HSV-1 genome, which contains at least 77 genes (GenBank) (31), makes experimental analyses challenging. To investigate whether any altered pathogenic properties of BgK L compared to those of BgO L and the rest of the isolates, referred to as non-BgK L : non-BgO L (8), were observed in different lesion sites, we further analyzed the RFLPs of clinical isolates from patients with ocular or genital HSV-1 infections. We then compared the frequency of each variant, referred to here as the variant relative frequency (RF), in the different lesion site groups of HSV-1 isolates.…”