Cytomegaloviruses are the prototypic members of the betaherpesvirus subgroup. Like all herpesviruses, they share several characteristics with other viruses of the family, including virion structure and the ability to establish persistent and latent infections. What makes the betaherpesvirus subgroup unique among the herpesviruses is their tropism for the salivary gland, their species specificity, and their slow growth in culture systems (25). Weller et al. coined the term cytomegalovirus to reflect the cytopathic effect caused by virus infection and the virus's role in genitally acquired cytomegalic inclusion disease (75).Human cytomegalovirus (HCMV) infection is generally asymptomatic in immunocompetent hosts. Typically, HCMV is acquired subclinically during childhood and persists throughout the individual's life. Persistence is characterized by the presence of latent viral genomes that periodically reactivate to produce infectious virus that can be shed intermittently in saliva, urine, semen, cervical secretions, and breast milk (25). Data suggest that persistence is established not only by the virus's ability to infect various cell types within the host, but also by the virus's ability to differentially regulate gene expression and by virally encoded immunomodulators (23,30,32,43,44,57,60,64). When primary HCMV infection is acquired during adulthood, the virus is capable of doing considerably more damage. In particular, primary infections during pregnancy can lead to congenital abnormalities in the fetus and morbidity and mortality in immunocompromised individuals, including transplant patients and persons with AIDS.Thus, with advances in medical procedures such as organ allografting and immunosuppressive posttransplant therapies as well as with increasing numbers of people infected with the human immunodeficiency virus (HIV), HCMV is proving to be a significant pathogen. Currently, the only Food and Drug Administration-approved antiviral therapies include the drugs ganciclovir, foscarnet, and cidofovir, each of which targets the viral DNA polymerase, and Vitravene, a novel antisense compound used to treat CMV retinitis (38). Although helpful, these drugs have numerous drawbacks, which include limited efficacy and toxic side effects and frequent emergence of resistant viral isolates during long-term therapy (17,19,72).Despite the growing information on HCMV gene products and pathogenesis, there is a limitation on the ability to develop effective treatments for primary HCMV infection or reactivation of latent infection. To address these limitations, four animal models are being evaluated for antiviral treatments against HCMV and for overall cytomegalovirus pathogenesis. These models are guinea pig cytomegalovirus, murine cytomegalovirus (MCMV), rat cytomegalovirus (RCMV), and more recently, rhesus cytomegalovirus (RhCMV). The guinea pig cytomegalovirus model is well suited for congenital cytomegalovirus infection because the virus can cross the placenta and produce infection in utero (31). Despite this advanta...
The possible role of amino acid sequence and epitope homologies between a protein P2-C of Coxsackie virus B4 and human GAD in the development of host-specific immune response in insulin-dependent diabetes mellitus (IDDM) (molecular mimicry) was investigated. Peptide antibodies to the P2-C protein, GAD65, and GAD67 were raised to analyze their immunoreactivity by enzyme-linked immunosorbent assay and immunoblotting with GAD purified from the brain and pancreas of mice that develop hyperglycemia after the infection. Additionally, antibody reactivity to these peptide antigens was assessed in sera from the virus-infected mice and IDDM patients. All three peptide antisera reacted very strongly with homologous peptides; P2-C antiserum cross-reacted with GAD65 as efficiently as GAD65 antiserum with P2-C, but no cross-reaction was detected between P2-C and GAD67 although cross-reaction between the two GADs was quite pronounced. P2-C antiserum immunocomplexed with GAD65 from mouse brain or pancreas, whereas GAD65 and GAD67 antisera both immunocomplexed with the two GADs from these sources. Most of the sera from virus-infected mice were reactive to brain and pancreas GAD65 and also to P2-C peptide, whereas some reacted to GAD65 and a few to GAD67 peptides. A number of IDDM sera reacted with mouse GAD65 and also with P2-C and GAD65 peptides, whereas only a few reacted with GAD67 peptide. The immunoreactivity of the mouse and IDDM sera to P2-C and GAD65 peptides was blocked by pre-adsorption with mouse GAD. The results suggest that molecular mimicry may play a role in the pathogenesis of the disease.
The human cytomegalovirus (HCMV) UL57 gene lies adjacent to HCMV oriLyt, from which it is separated by an organizationally conserved, mostly noncoding region that is thought to both regulate UL57 expression and activate oriLyt function. However, the UL57 promoter has not been studied. We determined the 5' ends of UL57 transcripts toward an understanding of the potential relationship between UL57 expression and oriLyt activation. The results presented here identified three distinct 5' ends spread over 800 bp, at nt 90302, 90530, and 91138; use of these sites exhibited differential sensitivity to phosphonoformic acid treatment. Interestingly, a 10-kb UL57 transcript accumulated in cycloheximide-treated infected cells, even though other early transcripts were not detectable. However, the 10-kb transcript did not accumulate in cells treated with the more stringent translation inhibitor anisomycin. Consistent with the notion that the identified 5' ends arise from distinct transcription start sites, the sequences upstream of sites I and II functioned as promoters responsive to HCMV infection in transient assays. However, the origin-proximal promoter region III required downstream sequences for transcriptional activity. Mutation of candidate core promoter elements suggested that promoter III is regulated by an initiator region (Inr) and a downstream promoter element. Finally, a 42-bp sequence containing the candidate Inr activated a minimal oriLyt core construct in transient replication assays. Thus, these studies showed that a large, complex promoter region with novel features controls UL57 expression, and identified a sequence that regulates both UL57 transcription and oriLyt activation.
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