Animal models of congenital cytomegalovirus infection: an overview of progress in the characterization of guinea pig cytomegalovirus (GPCMV)

Schleiss, Mark R.

doi:10.1016/s1386-6532(02)00100-2

Cited by 56 publications

(34 citation statements)

References 38 publications

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“…Thus, animal CMVs are generally used as mod-els to study CMV and CMV vaccines (32)(33)(34). Since host restriction resulted in coevolution of CMVs with their respective hosts, infection of rhesus macaques (RMs) with rhesus CMV (RhCMV) represents an animal model that closely resembles infection of humans with HCMV (35).…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

et al. 2014

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The most abundantly produced virion protein in human cytomegalovirus (HCMV) is the immunodominant phosphoprotein 65 (pp65), which is frequently included in CMV vaccines. Although it is nonessential for in vitro CMV growth, pp65 displays immunomodulatory functions that support a potential role in primary and/or persistent infection. To determine the contribution of pp65 to CMV infection and immunity, we generated a rhesus CMV lacking both pp65 orthologs (RhCMVΔpp65ab). While deletion of pp65ab slightly reduced growth in vitro and increased defective particle formation, the protein composition of secreted virions was largely unchanged. Interestingly, pp65 was not required for primary and persistent infection in animals. Immune responses induced by RhCMVΔpp65ab did not prevent reinfection with rhesus CMV; however, reinfection with RhCMVΔUS2-11, which lacks viral-encoded MHC-I antigen presentation inhibitors, was prevented. Unexpectedly, induction of pp65b-specific T cells alone did not protect against RhCMVΔUS2-11 challenge, suggesting that T cells targeting multiple CMV antigens are required for protection. However, pp65-specific immunity was crucial for controlling viral dissemination during primary infection, as indicated by the marked increase of RhCMVΔpp65ab genome copies in CMV-naive, but not CMV-immune, animals. Our data provide rationale for inclusion of pp65 into CMV vaccines but also demonstrate that pp65-induced T cell responses alone do not recapitulate the protective effect of natural infection.

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Section: Introductionmentioning

confidence: 99%

Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

et al. 2014

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“…Consequently, other target antigens should be considered important in the development of a vaccine against congenital CMV infection. The importance of other target antigens can be demonstrated in the guinea pig model, where a gB vaccine, despite high antibody titers, fails to fully protect against congenital CMV infection (51,56,57). The gH/gL complex has been identified as a potentially important target antigen, including in a congenital GPCMV infection model.…”

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confidence: 99%

A Novel Non-Replication-Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection

Choi

Root

McGregor

2016

J Virol

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Congenital cytomegalovirus (CMV) infection is a leading cause of mental retardation and deafness in newborns. The guinea pig is the only small animal model for congenital CMV infection. A novel CMV vaccine was investigated as an intervention strategy against congenital guinea pig cytomegalovirus (GPCMV) infection. In this disabled infectious single-cycle (DISC) vaccine strategy, a GPCMV mutant virus was used that lacked the ability to express an essential capsid gene (the UL85 homolog GP85) except when grown on a complementing cell line. In vaccinated animals, the GP85 mutant virus (GP85 DISC) induced an antibody response to important glycoprotein complexes considered neutralizing target antigens (gB, gH/gL/gO, and gM/gN). The vaccine also generated a T cell response to the pp65 homolog (GP83), determined via a newly established guinea pig gamma interferon enzyme-linked immunosorbent spot assay. In a congenital infection protection study, GP85 DISC-vaccinated animals and a nonvaccinated control group were challenged during pregnancy with wild-type GPCMV (10 5 PFU). The pregnant animals carried the pups to term, and viral loads in target organs of pups were analyzed. Based on live pup births in the vaccinated and control groups (94.1% versus 63.6%), the vaccine was successful in reducing mortality (P ‫؍‬ 0.0002). Additionally, pups from the vaccinated group had reduced CMV transmission, with 23.5% infected target organs versus 75.9% in the control group. Overall, these preliminary studies indicate that a DISC CMV vaccine strategy has the ability to induce an immune response similar to that of natural virus infection but has the increased safety of a non-replication-competent virus, which makes this approach attractive as a CMV vaccine strategy. IMPORTANCECongenital CMV infection is a leading cause of mental retardation and deafness in newborns. An effective vaccine against CMV remains an elusive goal despite over 50 years of CMV research. The guinea pig, with a placenta structure similar to that in humans, is the only small animal model for congenital CMV infection and recapitulates disease symptoms (e.g., deafness) in newborn pups. In this report, a novel vaccine strategy against congenital guinea pig cytomegalovirus (GPCMV) infection was developed, characterized, and tested for efficacy. This disabled infectious single-cycle (DISC) vaccine strategy induced a neutralizing antibody or a T cell response to important target antigens. In a congenital infection protection study, animals were protected against CMV in comparison to the nonvaccinated group (52% reduction of transmission). This novel vaccine was more effective than previously tested gB-based vaccines and most other strategies involving live virus vaccines. Overall, the DISC vaccine is a safe and promising approach against congenital CMV infection. H uman cytomegalovirus (HCMV), a betaherpesvirus, has evolved very closely with its human host. Virus infection in a healthy host is normally asymptomatic but leads to a lifelong infection. In contrast,...

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“…Human CMV is an important pathogen, causing neurological damage following congenital infection (37) as well as opportunistic infections in immunocompromised individuals. Models of human CMV pathogenesis and immune control have employed related betaherpesviruses that naturally infect guinea pigs (42), rats (8), and mice (21,25). The initial annotation of a laboratory-propagated human CMV strain, AD169 (10), predicted 194 unique open reading frames (ORFs).…”

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confidence: 99%

Predicting Coding Potential from Genome Sequence: Application to Betaherpesviruses Infecting Rats and Mice

Brocchieri¹,

Kledal

Karlin³

et al. 2005

J Virol

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Prediction of protein-coding regions and other features of primary DNA sequence have greatly contributed to experimental biology. Significant challenges remain in genome annotation methods, including the identification of small or overlapping genes and the assessment of mRNA splicing or unconventional translation signals in expression. We have employed a combined analysis of compositional biases and conservation together with frame-specific G؉C representation to reevaluate and annotate the genome sequences of mouse and rat cytomegaloviruses. Our analysis predicts that there are at least 34 protein-coding regions in these genomes that were not apparent in earlier annotation efforts. These include 17 single-exon genes, three new exons of previously identified genes, a newly identified four-exon gene for a lectin-like protein (in rat cytomegalovirus), and 10 probable frameshift extensions of previously annotated genes. This expanded set of candidate genes provides an additional basis for investigation in cytomegalovirus biology and pathogenesis.Sequence analysis has been crucial to understanding the biology of cytomegalovirus (CMV) as well as other herpesviruses (13,30). Human CMV is an important pathogen, causing neurological damage following congenital infection (37) as well as opportunistic infections in immunocompromised individuals. Models of human CMV pathogenesis and immune control have employed related betaherpesviruses that naturally infect guinea pigs (42), rats (8), and mice (21, 25). The initial annotation of a laboratory-propagated human CMV strain, AD169 (10), predicted 194 unique open reading frames (ORFs). Following this report, reevaluation of genome organization has occurred through correction of errors in the AD169 strain sequence (12,31,35,43), recognition of mRNA splicing events (15, 39), and empirical identification of genes that had escaped annotation (3,24,26). The human CMV sequence has been updated through analyses of additional strains (9,16,17,33) as well as by comparison to rhesus CMV (20) and chimpanzee CMV (14) genome sequences. Several revisions of the full genome complement of natural CMV have resulted from these studies. The number of genes in human CMV was estimated to range from under 150 to over 200 genes, and the current estimate of 165 genes is considered reasonable (16). Different estimates depend on the information considered, including homology with other genes in available databases, codon bias, preservation of known protein motifs, and the presence of transcription signals (13, 32).The annotated human CMV (HCMV) genome sequence has formed a basis for comparisons to other betaherpesviruses. Murine CMV (MCMV) (40) and rat CMV (RCMV) (45) retain obvious sequence homologs of about 80 HCMV ORFs, or roughly 50% of the annotated genes in these viruses. Non-CMV betaherpesviruses infecting humans, such as herpesvirus 6 (19) and herpesvirus 7 (36), as well as those infecting lower primates, such as herpesvirus tupaia (2), retain similar core sets of ORFs. Approximately 40 of these ...

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Animal models of congenital cytomegalovirus infection: an overview of progress in the characterization of guinea pig cytomegalovirus (GPCMV)

Cited by 56 publications

References 38 publications

Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

A Novel Non-Replication-Competent Cytomegalovirus Capsid Mutant Vaccine Strategy Is Effective in Reducing Congenital Infection

Predicting Coding Potential from Genome Sequence: Application to Betaherpesviruses Infecting Rats and Mice

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