Cloning and characterization of rhesus cytomegalovirus glycoprotein B.

Kravitz, Rachel H.; Sciabica, Kathryn S.; Cho, Ki-Ho; Luciw, Paul A.; Barry, Peter A.

doi:10.1099/0022-1317-78-8-2009

Cited by 24 publications

(19 citation statements)

References 16 publications

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“…For example, the gBs of MCMV and RCMV have 45 and 60% overall homology, respectively, to HCMV gB (33,34,46). Locally, there are regions of these gBs having much greater identity with the corresponding region of HCMV gB.…”

Section: Vol 78 2004 Small Molecule Inhibitor Of Hcmv Fusion 1295mentioning

confidence: 99%

“…gB-based fusion assays with either antibodies mapping to gp55, or various gp55 mutants, have indicated that this region plays an essential role in penetration (4,41,53,54). Resistance-conferring mutations G733S and F751L are within regions of high homology with gB of MCMV and RCMV; in both of these betaherpesvirus examples, the wild-type HCMV amino acid is conserved (33,34,46). The fact that CFI02 does not inhibit MCMV or RCMV indicates that the gB-CFI02 interaction requires more than just a single contact or interaction domain.…”

Section: Vol 78 2004 Small Molecule Inhibitor Of Hcmv Fusion 1295mentioning

confidence: 99%

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Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Jones

Lee²,

Johann³

et al. 2004

J Virol

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A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.

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Section: Vol 78 2004 Small Molecule Inhibitor Of Hcmv Fusion 1295mentioning

confidence: 99%

Section: Vol 78 2004 Small Molecule Inhibitor Of Hcmv Fusion 1295mentioning

confidence: 99%

Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Jones

Lee²,

Johann³

et al. 2004

J Virol

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“…Primer and probe sequences were designed to the glycoprotein B gene (UL55) of RhCMV (accession no. U41526) (12) by using the Primer Express program (version 1.0). The forward and reverse primer sequences were 5Ј-TGC GTA CTA TGG AAG AGA CAA TGC-3Ј and 5Ј-ACA TCT GGC CGT TCA AAA AAA C-3Ј, respectively.…”

Section: Methodsmentioning

confidence: 99%

Experimental Coinfection of Rhesus Macaques with Rhesus Cytomegalovirus and Simian Immunodeficiency Virus: Pathogenesis

Sequar¹,

Britt

Lakeman

et al. 2002

J Virol

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Human cytomegalovirus (HCMV) possesses low pathogenic potential in an immunocompetent host. In the immunosuppressed host, however, a wide spectrum of infection outcomes, ranging from asymptomatic to life threatening, can follow either primary or nonprimary infection. The variability in the manifestations of HCMV infection in immunosuppressed individuals implies that there is a threshold of host antiviral immunity that can effectively limit disease potential. We used a nonhuman primate model of CMV infection to assess the relationship between CMV disease and the levels of developing anti-CMV immunity. Naive rhesus macaques were inoculated with rhesus cytomegalovirus (RhCMV) followed 2 or 11 weeks later by inoculation with pathogenic simian immunodeficiency virus SIVmac239. Two of four monkeys inoculated with SIV at 2 weeks after inoculation with RhCMV died within 11 weeks with simian AIDS (SAIDS), including activated RhCMV infection. Neither animal had detectable anti-SIV antibodies. The other two animals died 17 and 27 weeks after SIV inoculation with either SAIDS or early lymphoid depletion, although no histological evidence of activated RhCMV was observed. Both had weak anti-SIV antibody titers. RhCMV antibody responses for this group of monkeys were significantly below those of control animals inoculated with only RhCMV. In addition, all animals of this group had persistent RhCMV DNA in plasma and high copy numbers of RhCMV in tissues. In contrast, animals that were inoculated with SIV at 11 weeks after RhCMV infection rarely exhibited RhCMV DNA in plasma, had low copy numbers of RhCMV DNA in most tissues, and did not develop early onset of SAIDS or activated RhCMV. SIV antibody titers were mostly robust and sustained in these monkeys. SIV inoculation blunted further development of RhCMV humoral responses, unlike the normal pattern of development in control monkeys following RhCMV inoculation. Anti-RhCMV immunoglobulin G levels and avidity were slightly below control values, but levels maintained were higher than those observed following SIV infection at 2 weeks after RhCMV inoculation. These findings demonstrate that SIV produces long-lasting insults to the humoral immune system beginning very early after SIV infection. The results also indicate that anti-RhCMV immune development at 11 weeks after infection was sufficient to protect the host from acute RhCMV sequelae following SIV infection, in contrast to the lack of protection afforded by only 2 weeks of immune response to RhCMV. As previously observed, monkeys that were not able to mount a significant immune response to SIV were the most susceptible to SAIDS, including activated RhCMV infection. Rapid development of SAIDS in animals inoculated with SIV 2 weeks after RhCMV inoculation suggests that RhCMV can augment SIV pathogenesis, particularly during primary infection by both viruses.

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“…gB, a major target of anti-HCMV antibodies, is also well conserved in RhCMV. The cloned RhCMV gB is proteolytically processed similarly to HCMV gB, portions of RhCMV gB cross-react with anti-HCMV gB antibodies, and RhCMV gB antibodies can be detected during RhCMV infection [56,57]. Phosphoprotein 65 (pp65) is another dominant target for the immune response to HCMV.…”

Section: Functional Characterizations Of Rhcmv Proteinsmentioning

confidence: 99%

Rhesus CMV: an emerging animal model for human CMV

Powers

Früh

2008

Med Microbiol Immunol

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Human CMV is the predominant infectious cause of congenital birth defects and an opportunistic pathogen in immunosuppressed individuals, including AIDS patients. Most individuals are infected early during their life followed by life-long latent infection. During this latent phase, frequent reactivation and antigen production continue to stimulate the immune system. While the immune response is able to control the virus, it is unable to eradicate it. Moreover, super-infection by diVerent CMV strains has been observed despite a strong immune response. Longterm immune stimulation by CMV has also been implicated in immune senescence and chronic conditions such as atherosclerosis. CMVs are highly species-speciWc and the relatedness of CMV genomes exactly mirrors the relatedness of their hosts. Thus, each CMV species is highly adapted to its respective host species, but is unable to infect other, even closely related hosts. While fascinating from an evolutionary perspective, this host restriction prevents studying HCMV in experimental animals. Exceptions are severely immunocompromised mice, e.g. SCID mice, or SCID/NOD mice, which might allow partial reconstitution of CMV infection in rodents. More practical however, is to study CMVs in their natural host, e.g. murine, rat or guinea pig CMVs. However, while these small animal models have many advantages, such as the availability of inbred animals as well as lower cost, the limited homology of the viral genomes with HCMV limits the functional analysis of homologous gene products. The closest relative to HCMV is chimpanzee CMV (CCMV), but this is not a practical animal model since chimps are a protected species, extremely expensive and of very limited availability. In contrast, rhesus macaques are a more widely used experimental animal species and, while more distant than CCMV, rhesus CMV (RhCMV) contains most of the HCMV gene families thus allowing the study of their role in acute and latent CMV infection. In this review we will discuss the current state of developing RhCMV as a model for HCMV.

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Cloning and characterization of rhesus cytomegalovirus glycoprotein B.

Cited by 24 publications

References 16 publications

Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Experimental Coinfection of Rhesus Macaques with Rhesus Cytomegalovirus and Simian Immunodeficiency Virus: Pathogenesis

Rhesus CMV: an emerging animal model for human CMV

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