Roseolovirus
Herpesvirus 7, Human
Differences in DNA binding specificity among Roseolovirus origin binding proteins. (1/18)
The Roseolovirus genus of the Betaherpesvirinae consists of the very closely related viruses, human herpesvirus 6 variants A and B (HHV-6A and HHV-6B) plus the somewhat more distantly related human herpesvirus 7 (HHV-7). The roseoloviruses each encode a homolog of the alphaherpesvirus origin binding protein (OBP) which is required for lytic DNA replication. In contrast, members of the other betaherpesvirus genera, the cytomegaloviruses, initiate DNA replication by a different mechanism. To better understand the basis of roseolovirus OBP sequence specificity, we investigated their ability to recognize each other's binding sites. HHV-6A OBP (OBP(H6A)) and HHV-6B OBP (OBP(H6B)) each bind to both of the HHV-7 OBP sites (OBP-1 and OBP-2) with similar strengths, which are also similar to their nearly equivalent interactions with their own sites. In contrast, HHV-7 OBP (OBP(H7)) had a gradient of binding preferences: HHV-7 OBP-2 > HHV-6 OBP-2 > HHV-7 OBP-1 > HHV-6 OBP-1. Thus, the roseolovirus OBPs are not equally reciprocal in their recognition of each other's OBP sites, suggesting that the sequence requirements for the interaction of OBPH7 at the OBP sites in its cognate oriLyt differ from those of OBPH6A and OBPH6B. (+info)A macrophage inflammatory protein homolog encoded by guinea pig cytomegalovirus signals via CC chemokine receptor 1. (2/18)
Cytomegaloviruses encode homologs of cellular immune effector proteins, including chemokines (CKs) and CK receptor-like G protein-coupled receptors (GPCRs). Sequence of the guinea pig cytomegalovirus (GPCMV) genome identified an open reading frame (ORF) which predicted a 101 amino acid (aa) protein with homology to the macrophage inflammatory protein (MIP) subfamily of CC (beta) CKs, designated GPCMV-MIP. To assess functionality of this CK, recombinant GPCMV-MIP was expressed in HEK293 cells and assayed for its ability to bind to and functionally interact with a variety of GPCRs. Specific signaling was observed with the hCCR1 receptor, which could be blocked with hMIP -1alpha in competition experiments. Migration assays revealed that GPCMV-MIP was able to induce chemotaxis in hCCR1-L1.2 cells. Antisera raised against a GST-MIP fusion protein immunoprecipitated species of approximately 12 and 10 kDa from GPCMV-inoculated tissue culture lysates, and convalescent antiserum from GPCMV-infected animals was immunoreactive with GST-MIP by ELISA assay. These results represent the first substantive in vitro characterization of a functional CC CK encoded by a cytomegalovirus. (+info)Preconception vaccination with a glycoprotein B (gB) DNA vaccine protects against cytomegalovirus (CMV) transmission in the guinea pig model of congenital CMV infection. (3/18)
DNA vaccines expressing the guinea pig cytomegalovirus (GPCMV) homologs of the glycoprotein B (gB) and UL83 proteins were evaluated for protection against congenital GPCMV infection. After 4 doses of DNA administered by epidermal (gene gun) route, all guinea pigs developed enzyme-linked immunosorbent assay (ELISA) antibody and, for gB-vaccine recipients, neutralizing antibody. Dams were challenged with 1 x 10(4) plaque-forming units of GPCMV in the third trimester. Preconception vaccination with gB did not decrease overall pup mortality, although, within the gB-vaccine group, pup mortality was lower among dams with high ELISA responses. Preconception maternal vaccination with gB vaccine significantly reduced congenital transmission in liveborn pups. In contrast, UL83 vaccine had no significant effect on pup mortality or vertical transmission of GPCMV. Virus load was significantly lower in infected pups born to gB- and UL83-vaccinated dams than in infected pups born to control dams. These data support the concept that subunit gB vaccination may be useful in protecting against CMV-induced disease. (+info)Dramatic effects of 2-bromo-5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole riboside on the genome structure, packaging, and egress of guinea pig cytomegalovirus. (4/18)
The halogenated benzimidazoles BDCRB (2-bromo-5,6-dichloro-1-beta-D-riborfuranosyl benzimidazole riboside) and TCRB (2,5,6-trichloro-1-beta-D-riborfuranosyl benzimidazole riboside) were the first compounds shown to inhibit cleavage and packaging of herpesvirus genomes. Both inhibit the formation of unit length human cytomegalovirus (HCMV) genomes by a poorly understood mechanism (M. R. Underwood et al., J. Virol. 72:717-715, 1998; P. M. Krosky et al., J. Virol. 72:4721-4728, 1998). Because the simple genome structure of guinea pig cytomegalovirus (GPCMV) provides a useful model for the study of herpesvirus DNA packaging, we investigated the effects of BDCRB on GPCMV. GPCMV proved to be sensitive to BDCRB (50% inhibitory concentration = 4.7 microM), although somewhat less so than HCMV. In striking contrast to HCMV, however, a dose of BDCRB sufficient to reduce GPCMV titers by 3 logs (50 microM) had no effect on the quantity of GPCMV genomic DNA that was formed in infected cells. Electron microscopy revealed that this DNA was in fact packaged within intranuclear capsids, but these capsids failed to egress from the nucleus and failed to protect the DNA from nuclease digestion. The terminal structure of genomes formed in the presence of BDCRB was also altered. Genomes with ends lacking a terminal repeat at the right end, which normally exist in an equimolar ratio with those having one copy of the repeat at the right end, were selectively eliminated by BDCRB treatment. At the left end, BDCRB treatment appeared to induce heterogeneous truncations such that 2.7 to 4.9 kb of left-end-terminal sequences were missing. These findings suggest that BDCRB induces premature cleavage events that result in truncated genomes packaged within capsids that are permeable to nuclease. Based on these and other observations, we propose a model for duplication of herpesvirus terminal repeats during the cleavage and packaging process that is similar to one proposed for bacteriophage T7 (Y. B. Chung, C. Nardone, and D. C. Hinkle, J. Mol. Biol. 216:939-948, 1990). (+info)Molecular, biological, and in vivo characterization of the guinea pig cytomegalovirus (CMV) homologs of the human CMV matrix proteins pp71 (UL82) and pp65 (UL83). (5/18)
We recently identified the genes encoding the guinea pig cytomegalovirus (GPCMV) homologs of the upper and lower matrix proteins of human CMV, pp71 (UL82) and pp65 (UL83), which we designated GP82 and GP83, respectively. Transient-expression studies with a GP82 plasmid demonstrated that the encoded protein targets the nucleus and that the infectivity and plaquing efficiency of cotransfected GPCMV viral DNA was enhanced by GP82. The transactivation function of GP82 was not limited to GPCMV, but was also observed for a heterologous virus, herpes simplex virus type 1 (HSV-1). This was confirmed by its ability to complement the growth of an HSV-1 VP16 transactivation-defective mutant virus in an HSV viral DNA cotransfection assay. Study of a GP82 "knockout" virus (and its attendant rescuant), generated on a GPCMV bacterial artificial chromosome construct, confirmed the essential nature of the gene. Conventional homologous recombination was used to generate a GP83 mutant to examine the role of GP83 in the viral life cycle. Comparison of the one-step growth kinetics of the GP83 mutant (vAM409) and wild-type GPCMV indicated that GP83 protein is not required for viral replication in tissue culture. The role of GP83 in vivo was examined by comparing the pathogenesis of wild-type GPCMV, vAM409, and a control virus, vAM403, in guinea pigs. The vAM409 mutant was significantly attenuated for dissemination in immunocompromised strain 2 guinea pigs, suggesting that the GP83 protein is essential for full pathogenicity in vivo. (+info)Cyclic cidofovir (cHPMPC) prevents congenital cytomegalovirus infection in a guinea pig model. (6/18)
BACKGROUND: Congenital cytomegalovirus (CMV) infection is a major public health problem. Antiviral therapies administered during pregnancy might prevent vertical CMV transmission and disease in newborns, but these agents have not been evaluated in clinical trials. The guinea pig model of congenital CMV infection was therefore used to test the hypothesis that antiviral therapy, using the agent agent cyclic cidofovir (cHPMPC), could prevent congenital CMV infection. RESULTS: Pregnant outbred Hartley guinea pigs were challenged in the early-third trimester with guinea pig CMV (GPCMV) and treated with placebo, or the antiviral agent, cyclic cidofovir. To optimize detection of vertical infection, an enhanced green fluorescent protein (eGFP)-tagged virus was employed. Compared to placebo, cyclic cidofovir-treated dams and pups had reduced mortality following GPCMV challenge. The magnitude of GPCMV-induced maternal and fetal mortality in this study was reduced from 5/25 animals in the placebo group to 0/21 animals in the treatment group (p = 0.05, Fisher's exact test). By viral culture assay, antiviral therapy was found to completely prevent GPCMV transmission to the fetus. In control pups, 5/19 (26%) were culture-positive for GPCMV, compared to 0/16 of pups in the cyclic cidofovir treatment group (p < 0.05, Fisher's exact test). CONCLUSION: Antiviral therapy with cyclic cidofovir improves pregnancy outcomes in guinea pigs, and eliminates congenital CMV infection, following viral challenge in the third trimester. This study also demonstrated that an eGFP-tagged recombinant virus, with the reporter gene inserted into a dispensable region of the viral genome, retained virulence, including the potential for congenital transmission, facilitating tissue culture-based detection of congenital infection. These observations provide support for clinical trials of antivirals for reduction of congenital CMV infection. (+info)Cloning the complete guinea pig cytomegalovirus genome as an infectious bacterial artificial chromosome with excisable origin of replication. (7/18)
(+info)Establishment of a cell-based assay for screening of compounds inhibiting very early events in the cytomegalovirus replication cycle and characterization of a compound identified using the assay. (8/18)
(+info)Roseolovirus is a genus of viruses in the family Herpesviridae, subfamily Betaherpesvirinae. The genus contains three species: Human herpesvirus 6A (HHV-6A), Human herpesvirus 6B (HHV-6B), and Human herpesvirus 7 (HHV-7). These viruses are closely related and cause similar diseases, most notably exanthema subitum or roseola in infants and young children.
The primary infection with HHV-6A and HHV-6B typically occurs during the first two years of life and is usually asymptomatic or associated with mild symptoms such as fever and rash (roseola). After the primary infection, the virus becomes latent in the host's immune cells and may reactivate later in life, causing various clinical manifestations, including febrile illnesses, seizures, and central nervous system disorders.
HHV-7 is also a common infectious agent in humans, primarily causing exanthema subitum or roseola in children. It can also establish latency and reactivate, although its association with specific diseases is less clear than that of HHV-6A and HHV-6B.
Overall, Roseolovirus species are important human pathogens, particularly during early childhood, and may contribute to various clinical manifestations throughout life.
Human Herpesvirus 7 (HHV-7) is a species of the Herpesviridae family and Betaherpesvirinae subfamily. It is a double-stranded DNA virus that primarily infects human hosts. HHV-7 is closely related to Human Herpesvirus 6 (HHV-6) and both viruses share many biological and biochemical properties.
HHV-7 is typically acquired in early childhood, with most people becoming infected before the age of five. Primary infection with HHV-7 can cause a mild illness known as exanthema subitum or roseola infantum, which is characterized by fever and a rash. However, many HHV-7 infections are asymptomatic.
After initial infection, HHV-7 becomes latent in the host's immune cells, particularly CD4+ T-lymphocytes. The virus can reactivate later in life, causing various clinical manifestations such as chronic fatigue syndrome, seizures, and exacerbation of atopic dermatitis. HHV-7 has also been implicated in the development of certain malignancies, including lymphoproliferative disorders and some types of brain tumors.
Like other herpesviruses, HHV-7 establishes a lifelong infection in its human host, with periodic reactivation throughout the individual's lifetime.
Roseolovirus infections are typically caused by human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). The most common manifestation of roseolovirus infection is exanthem subitum, also known as roseola infantum or sixth disease, which primarily affects children aged 6 months to 2 years.
The infection usually begins with a fever that can last for up to a week, followed by the appearance of a rash once the fever subsides. The rash is typically pinkish-red, maculopapular (consisting of both flat and raised lesions), and appears on the trunk, spreading to the face, neck, and extremities. It usually lasts for 1-2 days.
In addition to exanthem subitum, roseolovirus infections can also cause a variety of other clinical manifestations, including febrile seizures, hepatitis, pneumonitis, myocarditis, and encephalitis. HHV-6 and HHV-7 have also been associated with several chronic diseases, such as chronic fatigue syndrome, multiple sclerosis, and certain malignancies.
Transmission of roseolovirus occurs through saliva and other bodily fluids, and primary infection is usually acquired during childhood. Once infected, the virus remains latent in the body and can reactivate later in life, although reactivation rarely causes symptoms.