Glycoprotein B genotype correlates with cell tropism in vivo of human cytomegalovirus infection

Meyer‐König, Ursula; Vogelberg, Christian; Bongarts, Angela; Kampa, Danielle; Delbrück, Regine; Wolff-Vorbeck, Guido; Kirste, Günter; Haberland, Michael; Hufert, Frank T.; Laer, Dorotheé von

doi:10.1002/(sici)1096-9071(199805)55:1<75::aid-jmv12>3.0.co;2-z

Cited by 90 publications

(56 citation statements)

References 32 publications

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“…The underlying biologic explanations of these patterns could be varied. Cellular tropism is a possible candidate, particularly because the contribution of HCMV glycoproteins to cellular tropism is well-established (80)(81)(82)(83), and genetic variation in genes encoding glycoproteins may play a role in altering HCMV tropism in vivo (27,28). Thus, it is possible that at least a portion of the plasma-enriched SNPs identified in the current study alter HCMV tropism.…”

Section: Discussionmentioning

confidence: 99%

“…For example, genetic variation in the gO locus alters the ratio of the gH/gL/UL128-131 and gH/gL/gO complexes and is proposed to influence endothelial and fibroblast cell tropism and dissemination (27). Likewise, various gB (UL55) genotypes are preferentially associated with host compartments, suggesting a role for gB variation in tropism (28). Lastly, positive selection targets glycoproteins during viral dissemination from plasma to urine (11), suggesting a link between variable viral genetics and fitness in different host compartments.…”

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confidence: 83%

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Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

113

129

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Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.human cytomegalovirus | HCMV | congenital CMV | virology | evolution

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

113

129

View full text Add to dashboard Cite

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“…In three patients the restriction pattern could not be assigned to one of the four gBcls types, indicating the presence of two or more genotypes in one blood sample. To resolve the mixture of gBcls types in these samples, a PCR-based limited dilution RFLP assay was performed as described previously (Meyer-Ko$ nig et al, 1998 c). Briefly, tenfold dilutions of the first round amplification product were made up to the point where only 50 % of several second round amplifications gave a positive signal.…”

Section: Detection Of Homologous Recombination In Doubleinfected Patimentioning

confidence: 99%

Variation within the glycoprotein B gene of human cytomegalovirus is due to homologous recombination.

Haberland¹,

Meyer-K√∂nig²,

Hufert³

1999

Journal of General Virology

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Human cytomegalovirus (HCMV) strains can be classified into different glycoprotein B (gB) genotypes. In a previous study, frequent intragenic variation of the gB gene was shown. The aim of this study was to analyse whether gB variation was due to homologous recombination. The gB gene of DNA extracts derived from the peripheral blood leukocytes of 14 immunosuppressed patients was amplified by PCR and cloned. Three variable sites of gB were analysed by restriction fragment analysis and DNA sequencing and compared with published prototypic strains. In three patients doubly infected with two distinct HCMV gB strains, prototypic (60-85 %) and nonprototypic recombinant strains (5-40 %) were detected. To demonstrate that homologous recombination is driving HCMV gB variability, cells were coinfected with plaque-purified prototypic gB strains and recombinant gB genes were selectively amplified by PCR. gB recombinants were detected after 15 days of coculture and cross-over sites were determined by sequencing. These data indicate that homologous recombination contributes to the variability of the gB gene in vitro and in vivo.

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“…Mutations in gB also altered neuroinvasion in a mouse footpad infection model (48). In human cytomegalovirus, differences in gB genes correlated with viral tropism in vivo and virulence (29). To investigate the role of gB in infection of a natural herpesvirus-host system, wild-type PrV, the BHV-1 gB recombinant PrV-9112C2, and a matching revertant in which the BHV gene was replaced by the parental pseudorabies gene were compared after intranasal infection of pigs.…”

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confidence: 99%

Pseudorabies Virus Expressing Bovine Herpesvirus 1 Glycoprotein B Exhibits Altered Neurotropism and Increased Neurovirulence

Gerdts¹,

Beyer

Lomniczi

et al. 2000

J Virol

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Herpesvirus glycoproteins play dominant roles in the initiation of infection of target cells in culture and thus may also influence viral tropism in vivo. Whereas the relative contribution of several nonessential glycoproteins to neurovirulence and neurotropism of Pseudorabies virus (PrV), an alphaherpesvirus which causes Aujeszky's disease in pigs, has recently been uncovered in studies using viral deletion mutants, the importance of essential glycoproteins is more difficult to assess. We isolated an infectious PrV mutant, PrV-9112C2, which lacks the gene encoding the essential PrV glycoprotein B (gB) but stably carries in its genome and expresses the homologous gene of bovine herpesvirus 1 (BHV-1) (A. Kopp and T. C. Mettenleiter, J. Virol. 66:2754-2762, 1992). Apart from exhibiting a slight delay in penetration kinetics, PrV-9112C2 was similar in its growth characteristics in cell culture to wild-type PrV. To analyze the effect of the exchange of these homologous glycoproteins in PrV's natural host, swine, 4-week-old piglets were intranasally infected with 10 6 PFU of either wild-type PrV strain Kaplan (PrV-Ka), PrV-9112C2, or PrV-9112C2R, in which the PrV gB gene was reinserted instead of the BHV-1 gB gene. Animals infected with PrV-Ka and PrV-9112C2R showed a similar course of disease, i.e., high fever, marked respiratory symptoms but minimal neurological disorders, and excretion of high amounts of virus. All animals survived the infection. In contrast, animals infected with PrV-9112C2 showed no respiratory symptoms and developed only mild fever. However, on day 5 after infection, all piglets developed severe central nervous system (CNS) symptoms leading to death within 48 to 72 h. Detailed histological analyses showed that PrV-9112C2R infected all regions of the nasal mucosa and subsequently spread to the CNS preferentially by the trigeminal route. In contrast, PrV-9112C2 primarily infected the olfactory epithelium and spread via the olfactory route. In the CNS, more viral antigen and significantly more pronounced histological changes resulting in more severe encephalitis were found after PrV-9112C2 infection. Thus, our results demonstrate that replacement of PrV gB by the homologous BHV-1 glycoprotein resulted in a dramatic increase in neurovirulence combined with an alteration in the route of neuroinvasion, indicating that the essential gB is involved in determining neurotropism and neurovirulence of PrV.Pseudorabies virus (PrV) and Bovine herpesvirus 1 (BHV-1) are related alphaherpesviruses of the genus Varicellovirus. PrV, also designated Suid herpesvirus 1, is the causative agent of Aujeszky's disease (AD), a serious illness in domestic and wild animals. PrV has a broad host range and productively infects birds and most mammals, except for horses and higher primates including humans, which are resistant to infection (reviewed in reference 25). Whereas mortality in most infected species regularly amounts to 100%, pigs can survive a productive infection and remain latently infected for life. Thus, pigs a...

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Glycoprotein B genotype correlates with cell tropism in vivo of human cytomegalovirus infection

Cited by 90 publications

References 32 publications

Limits and patterns of cytomegalovirus genomic diversity in humans

Limits and patterns of cytomegalovirus genomic diversity in humans

Variation within the glycoprotein B gene of human cytomegalovirus is due to homologous recombination.

Pseudorabies Virus Expressing Bovine Herpesvirus 1 Glycoprotein B Exhibits Altered Neurotropism and Increased Neurovirulence

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