gpUL73 (gN) genomic variants of human cytomegalovirus isolates are clustered into four distinct genotypes

Abstract

Clinical isolates of human cytomegalovirus (HCMV) show differences in tissue tropism, severity of clinical manifestations and ability to establish persistent or latent infections, characteristics that are thought to be related to genomic variation among strains. This work analysed the genomic variants of a new HCMV polymorphic locus, open reading frame (ORF) UL73. This ORF encodes the envelope glycoprotein gpUL73 (gN), which associates in a high molecular mass complex with its counterpart, gM, and induces a neutralizing antibody response in the host. Detailed sequence analysis of ORF UL73 and its gene product from clinical isolates and laboratory-adapted strains shows that this glycoprotein is highly polymorphic, in the N-terminal region in particular. gpUL73 hypervariability is not randomly distributed, but the identified genomic variants are clearly clustered into four distinct genotypes (gN-1, gN-2, gN-3 and gN-4), which are not associated with the gB subtype.Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus with a broad spectrum of infectivity, as documented by the several different cell types that can be infected in vitro and by the multiple organ tropism observed during infection in vivo. Differences in tissue tropism, severity of clinical manifestations and ability to establish persistent or latent HCMV infections are thought to be related to genomic variability among strains (Brown et al., 1995 ;Fries et al., 1994 ; Meyer-Konig et al., 1998 a, b). The sequence similarity between different isolates varies depending on the region analysed (Bale et al., 1993) ; highly variable regions have been found in the HCMV genome.

Cytomegalovirus Strain Diversity in Seropositive Women

“…Similar to the results of previous studies, we did not observe a linkage between the gN and gB genotypes (11). However, the number of samples examined was small and we found only one sample that contained a single gN genotype and five samples containing a single variant of gB.…”

“…Of the 16 samples analyzed for gB genotypes, 69% (11/16) were found to contain more than one gB genotype; eight samples had two genotypes, and three samples had three genotypes ( Strains are grouped by comparing the sequences of the recombinants with the prototypic gN genotypes previously described (11). The sequences are listed with the unique study subject identifiers.…”

“…Recent studies have shown that a significant proportion of the virus-neutralizing response was also directed against the gM/gN complex (17). No linkage between gN genotypes and gB genotypes has been observed (11).…”

“…Published studies using RFLP analyses to determine the gN genotypes have identified only a single gN type in a given sample (11,13). Studies of glycoprotein B based on RFLP analyses showed the presence of a single genotype or a limited number of samples containing mixtures of two gB genotypes (3,7).…”

“…Major envelope glycoprotein B (gB) of CMV has been demonstrated to elicit a strong neutralizing antibody response (6), and on the basis of restriction fragment length polymorphism (RFLP) analysis of clinical samples, four unique genomic variants, gB types 1 to 4, have been identified (9). Glycoprotein N has been shown to be highly polymorphic at the amino-terminal region, and most clinical CMV isolates have been shown to cluster into four distinct genomic variants, gN-1, gN-2, gN-3a, gN-3b, gN-4a, gN-4b, and gN-4c (11). Recent studies have shown that a significant proportion of the virus-neutralizing response was also directed against the gM/gN complex (17).…”