A Homolog Pentameric Complex Dictates Viral Epithelial Tropism, Pathogenicity and Congenital Infection Rate in Guinea Pig Cytomegalovirus

Coleman, Stewart; Choi, K. Yeon; Root, Matthew; McGregor, Alistair

doi:10.1371/journal.ppat.1005755

Cited by 27 publications

(189 citation statements)

References 105 publications

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“…It has been well established for HCMV that, while gB is an important target of neutralizing antibodies, the majority of neutralization activity in seropositve individuals is directed against the gH/gL/ UL128-131A pentameric complex (47,48). Furthermore, the pentameric complex has also been shown to be a target of neutralizing antibodies for guinea pig CMV (49). In this study, we determined that antibodies targeting both RhgB and RhPC contribute to the total neutralization activity of RhCMV-seropositive monkey sera in approximately equivalent proportions (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

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Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

Nelson¹,

Cruz²,

Tran³

et al. 2017

JCI Insight

110

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Section: Discussionmentioning

confidence: 99%

“…The high-potency-infused animals were sampled at days 0, 1, 2, 3,4,7,10,14,21,28,35,42,49,56,63,70,77, and 84. Amniotic fluid (by amniocentesis), urine (by clean pan collection), and saliva (by oral saline wash), were also collected on all animals on a weekly to biweekly intervals until fetal harvest.…”

Section: Methodsmentioning

confidence: 99%

Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

Nelson¹,

Cruz²,

Tran³

et al. 2017

JCI Insight

110

View full text Add to dashboard Cite

“…In GPCMV, a homologous UL128-131 locus has been identified, and the ability to form a pentameric complex has been investigated (28,58). We recently demonstrated that this complex is important for virus tropism to epithelial cells, pathogenicity, and congenital infection (103). Importantly, the homolog pentameric complex is highly immunogenic (102).…”

Section: Discussionmentioning

confidence: 99%

“…The vaccine strategy was successful in fully preventing pup deaths and greatly reduced the level and incidence of pups with congenital CMV infection compared to a nonvaccinated control group. This promising vaccine strategy presents potential opportunities for improvement via the inclusion of the homolog pentameric complex, which is considered an important complex for virus infection of epithelial cells (103) and a variety of other cell types. The potential addition of neutralizing antibodies to this complex will greatly reduce congenital transmission.…”

Section: Discussionmentioning

confidence: 99%

“…We recently demonstrated that GPCMV forms functionally similar glycoprotein complexes, and these complexes are essential for infection of fibroblast cells as well as serving as important target antigens (36). Additionally, GPCMV forms a homologous pentameric complex (gH/gL/UL128-131) that is necessary for epithelial tropism in HCMV (45) and GPCMV (103) as well as other cell types (46).…”

mentioning

confidence: 99%

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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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Betaherpesvirus Virion Assembly and Egress

Anderson

Pellett

2018

Advances in Experimental Medicine and Biology

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Virions are the vehicle for cell-to-cell and host-to-host transmission of viruses. Virions need to be assembled reliably and efficiently, be released from infected cells, survive in the extracellular environment during transmission, recognize and then trigger entry of appropriate target cells, and disassemble in an orderly manner during initiation of a new infection. The betaherpesvirus subfamily includes four human herpesviruses (human cytomegalovirus and human herpesviruses 6A, 6B, and 7), as well as viruses that are the basis of important animal models of infection and immunity. Similar to other herpesviruses, betaherpesvirus virions consist of four main parts (in order from the inside): the genome, capsid, tegument, and envelope. Betaherpesvirus genomes are dsDNA and range in length from ~145 to 240 kb. Virion capsids (or nucleocapsids) are geometrically well-defined vessels that contain one copy of the dsDNA viral genome. The tegument is a collection of several thousand protein and RNA molecules packed into the space between the envelope and the capsid for delivery and immediate activity upon cellular entry at the initiation of an infection. Betaherpesvirus envelopes consist of lipid bilayers studded with virus-encoded glycoproteins; they protect the virion during transmission and mediate virion entry during initiation of new infections. Here, we summarize the mechanisms of betaherpesvirus virion assembly, including how infection modifies, reprograms, hijacks, and otherwise manipulates cellular processes and pathways to produce virion components, assemble the parts into infectious virions, and then transport the nascent virions to the extracellular environment for transmission.

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A Homolog Pentameric Complex Dictates Viral Epithelial Tropism, Pathogenicity and Congenital Infection Rate in Guinea Pig Cytomegalovirus

Cited by 27 publications

References 105 publications

Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

Preexisting antibodies can protect against congenital cytomegalovirus infection in monkeys

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

Betaherpesvirus Virion Assembly and Egress

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