[The effect of cornin on viral replication and DNA synthesis in mammalian cells].
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Animals↗
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Results for “viral replication”
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[Markers of viral replication (HBeAg and DNA polymerase activity) in chronic uremia, HBsAg positive, hemodialysis patients].
The contagiousness of hepatitis B virus (HBV) carriers with end-stage renal disease undergoing chronic hemodialysis has been ascribed to an immunologic tolerance for HBV antigens, especially hepatitis B core antigen, supporting persistently high levels of virus replication. In this context hepatitis B e antigen and core-associated DNA polymerase (DNA P) activity have proved to be distinct markers of HBV replication. In order to evaluate the potential infectivity of these subjects, thirty-five HBsAg positive hemodialysis patients were studied for the presence of HBeAg/anti-HBe system correlating the results with serum DNA P activity. Twenty out of 35 patients were HBeAg positive (57%) and 21 DNA P positive (60%). A highly significant correlation (P less than 0,001) was recorded between detection of HBeAg and presence of serum DNA P activity. These findings confirm that the majority of hemodialysis patients carrying HBsAg show high levels of virus replication so that the determination of HBeAg and DNA P activity other than HBsAg is required for the identification of patients highly infectious.
Chronic Disease↗
New perspectives on HIV pathogenesis. Viral replication is continuous throughout the course of disease.
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Adult↗
Altered tissue distribution of viral replication and T cell spreading is pivotal in the protection against fatal lymphocytic choriomeningitis in mice after neutralization of IFN-alpha/beta.
IFN-alpha/beta have been shown to play a central role in the development of lymphocytic choriomeningitis and increasing attention has been focused on this group of cytokines as early regulatory factors directing T lymphocyte responses. In the present study, injection of antiserum to IFN-alpha/beta prevented the development of lymphocytic choriomeningitis, was associated with the absence of detectable expression of early 2'-5' oligo-adenylate synthetase mRNA and coincided with viremia of lymphocytic choriomeningitis virus (LCMV) followed by establishment of a persistent infection. The LCMV-specific cytotoxic T lymphocyte response was unchanged in cervical lymph nodes but decreased in the spleen of anti-IFN-alpha/beta-treated animals. The expression of cytokine mRNA (particularly IFN-gamma) in organs of LCMV-infected mice treated with anti-IFN-alpha/beta coincided with infiltration of lymphocytes and tissue destruction. Furthermore, a reduced number of infiltrating leukocytes in the brain and cervical lymph nodes and a low expression of cytokine mRNA in the brain was observed in anti-IFN-alpha/beta-treated animals. In total, the findings support the view that neutralization of IFN-alpha/beta leads to extensive LCMV replication in the viscera. The therapeutic effects of anti-IFN-alpha/beta antiserum seem to be independent of the functional capacity of T cells but probably result in a dispersion of activated T cells throughout the body of LCMV-infected mice. Absence of IFN-alpha/beta expression in the central nervous system is proposed as the mechanism behind the IFN-alpha/beta-dependent targeting of T cells to the brain.
2',5'-Oligoadenylate Synthetase↗
New perspectives on HIV pathogenesis. Viral replication is continuous throughout the course of disease.
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CD4-Positive T-Lymphocytes↗
Long-term remission of HIV-associated thrombocytopenia parallels ongoing suppression of viral replication.
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Adult↗
The function(s) provided by the adenovirus-specified, DNA-binding protein required for viral late gene expression is independent of the role of the protein in viral DNA replication.
The adenovirus type 2 (Ad2) host range mutant Ad2hr400 grows efficiently in cultured monkey cells at 37 degrees C, but is cold sensitive for plaque formation and late gene expression at 32.5 degrees C. After nitrous acid mutagenesis of an Ad2hr400 stock, cold-resistant variants were selected in CV1 monkey cells at 32.5 degrees C. One such variant, Ad2ts400, was also temperature sensitive (ts) for growth in both CV1 and HeLa cells. Marker rescue analysis has been used to show that the two phenotypes, cold resistant and temperature sensitive, are due to two independent mutations, each of which resides in a different segment of the gene encoding the 72-kilodalton DNA binding protein (DBP). The cold-resistant mutation (map coordinates 63.6 to 66) is a host range alteration that enhances the ability of the virus to express late genes and grow productively in monkey cells at 32.5 degrees C. The temperature-sensitive mutation is in the same complementation group and maps to the same segment of the DBP gene (map coordinates 61.3 to 63.6) as the well-characterized DBP mutant Ad5ts125. Like Ad5ts125, Ad2ts400 is unable to replicate viral DNA or to properly shut off early mRNA expression at the nonpermissive temperature. Two sets of experiments with Ad2ts400 suggest that DBP contains separate functional domains. First, when CV1 cells are coinfected at the nonpermissive temperature with Ad2 plus Ad2ts400 (Ad2 allows DNA replication and entry into, but not completion of, the late phase of infection), normal late gene expression and productive growth occur. Second, temperature shift experiments show that, although DNA replication is severely restricted at the nonpermissive temperature in ts400-infected monkey cells, late gene expression occurs normally. These results indicate that the DBP activity required for normal late gene expression in monkey cells is functional even when the DBP's DNA replication activity is disrupted.
Adenoviridae↗
The capsid-associated UL25 protein of the alphaherpesvirus pseudorabies virus is nonessential for cleavage and encapsidation of genomic DNA but is required for nuclear egress of capsids.
Homologs of the UL25 gene product of herpes simplex virus (HSV) have been identified in all three subfamilies of the Herpesviridae. However, their exact function during viral replication is not yet known. Whereas earlier studies indicated that the UL25 protein of HSV-1 is not required for cleavage of newly replicated viral DNA but is necessary for stable encapsidation (A. R. McNab, P. Desai, S. Person, L. Roof, D. R. Thompson, W. W. Newcomb, J. C. Brown, and F. L. Homa, J. Virol. 72:1060-1070, 1998), viral DNA packaging has recently been demonstrated to occur in the absence of UL25, although at significantly decreased levels compared to wild-type HSV-1 (N. Stow, J. Virol. 75:10755-10765 2001). To clarify the functional role of UL25 we analyzed the homologous protein of the alphaherpesvirus pseudorabies virus (PrV). PrV UL25 was found to be essential for viral replication, as a mutant virus lacking the UL25 protein required UL25-expressing cells for productive propagation. In the absence of the UL25 protein, newly replicated PrV DNA was cleaved and DNA-containing C-type capsids were detected in infected cell nuclei. However, although capsids were frequently found in close association with the inner nuclear membrane, nuclear egress was not observed. Consequently, no capsids were found in the cytoplasm, resulting in an inhibition of virion morphogenesis. In contrast, the formation of capsidless enveloped tegument structures (L particles) in the cytoplasm was readily observed. Thus, our data demonstrate that the PrV UL25 protein is not essential for cleavage and encapsidation of viral genomes, although both processes occur more efficiently in the presence of the protein. However, the presence of the PrV UL25 protein is a prerequisite for nuclear egress. By immunoelectron microscopy, we detected UL25-specific label on DNA-containing C capsids but not on other intranuclear immature or defective capsid forms. Thus, the PrV UL25 protein may represent the hitherto missing trigger that allows primary envelopment preferably of DNA-filled C capsids.
Animals↗
Antibody response to influenza infection of mice: different patterns for glycoprotein and nucleocapsid antigens.
Our previous studies of C57BL/6 mice intranasally infected with influenza virus (A/PR8) revealed a spike of virus-specific immunoglobulin A (IgA)-secreting antibody-forming cells (AFC) in the mediastinal lymph node (MLN) 7 days post-infection. Here we show that these AFC are directed only against viral glycoprotein, and not nucleocapsid antigens. The early IgA spike associates with a decline in glycoprotein-specific AFC during week 2 post-infection. In contrast to the glycoprotein-specific AFC, nucleocapsid-specific, IgA-secreting AFC develop gradually in the MLN and persist for more than 3 weeks post-infection. As peripheral lymph node reactions wane, the nucleocapsid-specific AFC appear as long-sustained populations in the bone marrow. Microanatomical examination of the respiratory tract in infected mice shows foci of infection established in the lung 2 days post-infection, from which virus spreads to infect the entire lining of the trachea by day 3. At this time, viral haemagglutinin can be seen within the MLN, probably on projections from infected dendritic cells. This feature disappears within a day, though viral antigen expression continues to spread throughout the respiratory tract. Total IgA- and IgG-secreting AFC appear histologically in large numbers during the first week post-infection, significantly preceding the appearance of germinal centres (revealed by peanut agglutinin staining in week 2). To explain these results, we suggest that the initial immunogenic encounter of B cells with viral antigens occurs about 3 days post-infection in the MLN, with antigens transported by dendritic cells from airway mucosa, the only site of viral replication. Viral glycoproteins expressed as integral membrane components on the surface of infected dendritic cells [probably in the absence of cognate T helper (Th) cells] promote members of expanding relevant B-cell clones to undergo an IgA switch and terminal local plasmacytoid differentiation. Anti-glycoprotein specificities are thus selectively depleted from progeny of activated B-cell clones which are channelled to participate in germinal centre formation (perhaps by cognate T helper cells when they become sufficiently frequent). One product of the germinal centre reaction is the long-sustained, bone marrow-resident population, which is accordingly rich in anti-nucleoprotein, but not anti-glycoprotein specificities. Of note, we find that AFC responses toward influenza virus and Sendai virus differ, even though viral replication is limited to the airway mucosa in each case. The response towards Sendai virus exhibits neither the early appearance of anti-glycoprotein AFC expressing IgA in draining lymph nodes, nor the subsequent relative deficit of this specificity from bone marrow AFC populations.
Animals↗
The enigma of herpes stromal disease.
Herpes stromal disease is due to direct damage as a result of viral replication, virally induced immune mechanisms, or a combination of the two. Viral replication may have a major initiating role in the production of herpes simplex and herpes zoster induced stromal disease, and steroids may initially be harmful in their treatment. On topical antiviral drugs alone, in patients who never previously had had topical steroids, 14 of 15 cases of herpes simplex induced disciform keratitis responded favourably in an average of 44 days of treatment. This compared with one out of 14 responding if steroids had previously been used, 13 of 14 requiring topical steroids and an average 112 days' treatment. In herpes zoster stromal disease cases 78% had epithelial involvement, 54 of 57 responded to topical antivirals alone without the use of steroids, 2% recurred, and treatment averaged a total of 62 days. If steroids were used alone or in combination with antivirals, there was a 50% recurrence rate and 200 day total treatment duration.
Acyclovir↗
Variant upstream regulatory region sequences differentially regulate human papillomavirus type 16 DNA replication throughout the viral life cycle.
While the central role of the viral upstream regulatory region (URR) in the human papillomavirus (HPV) life cycle has been well established, its effects on viral replication factor expression and plasmid replication of HPV type 16 (HPV16) remain unclear. Some nonprototypic variants of HPV16 contain altered URR sequences and are considered to increase the oncogenic risk of infections. To determine the relationship between viral replication and variant URRs, hybrid viral genomes were constructed with the replication-competent HPV16 prototype W12 and analyzed in assays which recapitulate the different phases of normal viral replication. The establishment efficiencies of hybrid HPV16 genomes differed about 20-fold among European prototypes and variants from Africa and America. Generally, European and African genomes exhibited the lowest replication efficiencies. The high replication levels observed with American variants were primarily attributable to their efficient expression of the replication factors E1 and E2. The maintenance levels of these viral genomes varied about fivefold, which correlated with their respective establishment phenotypes and published P(97) activities. Vegetative DNA amplification could also be observed with replicating HPV16 genomes. These results indicate that efficient E1/E2 expression and elevated plasmid replication levels during the persistent stage of infection may comprise a risk factor in HPV16-mediated oncogenesis.
Cell Line↗
Combination of a hepatitis C virus NS3-NS4A protease inhibitor and alpha interferon synergistically inhibits viral RNA replication and facilitates viral RNA clearance in replicon cells.
The present standard of care for hepatitis C virus (HCV) infection is pegylated alpha interferon (IFN-alpha) in combination with ribavirin. However, specific antivirals such as HCV NS3-NS4A protease inhibitors are now in clinical development, and these agents can potentially be used in combination with the present treatments. Therefore, it is important to investigate the potential benefits or adverse effects of these new combinations by using available in vitro HCV culture systems first. In the present study we demonstrate that the combination of a specific HCV NS3-NS4A protease inhibitor and IFN-alpha synergistically inhibits HCV RNA replication in replicon cells, with little or no increase in cytotoxicity. Furthermore, the benefit of the combination was sustained over time, such that a greater than 3-log reduction in HCV RNA levels was achieved following 9 days of treatment. The viral RNA appeared to be cleared from the replicon cells after 14 days of treatment, and no viral RNA rebound was observed upon withdrawal of the inhibitors. In each case, the antiviral effects obtained with higher concentrations of either the protease inhibitor alone or IFN-alpha alone can be achieved by a combination of both agents at lower concentrations, which may potentially reduce the risk of possible adverse effects associated with high doses of either agent.
Antiviral Agents↗
Transient viral DNA replication and repression of viral transcription are supported by the C-terminal domain of the bovine papillomavirus type 1 E1 protein.
The bovine papillomavirus type 1 E1 protein is important for viral DNA replication and transcriptional repression. It has been proposed that the full-length E1 protein consists of a small N-terminal and a larger C-terminal domain. In this study, it is shown that an E1 polypeptide containing residues 132 to 605 (which represents the C-terminal domain) is able to support transient viral DNA replication, although at a level lower than that supported by the wild-type protein. This domain can also repress E2-mediated transactivation from the P89 promoter as well as the wild-type E1 protein can.
Amino Acid Sequence↗
Two segments in the genome of the immunosuppressive minute virus of mice determine the host-cell specificity, control viral DNA replication and affect viral RNA metabolism.
Two strains of minute virus of mice (MVM) show different host-cell specificities. MVM(i) grows in T lymphocytes whereas MVM(p) is fibroblast-specific. By constructing recombinant viral DNAs between the genomes of the two strains, we have shown that two segments of the MVM(i) genome are required for lytic viral growth in T lymphocytic EL4 cells. One segment (iE) was found between nucleotides 1084 and 2070, in a region encoding the early viral proteins and containing mRNA splice signals and the late P39 promoter. The other (iL) was between nucleotides 3523 and 4339 in the region coding for capsid protein. The P39 promoters within the E segment from MVM(i) or MVM(p) were equally active in transfected EL4 cells. However, pE-containing MVM DNA produced more NS2 mRNA than iE-containing DNA, apparently the result of virus-strain-specific differences in the regulation of splicing.
Amino Acid Sequence↗
A method of limited replication for the efficient in vivo delivery of adenovirus to cancer cells.
Replication-deficient viral vectors are currently being used in gene transfer strategies to treat cancer cells. Unfortunately, viruses are limited in their ability to diffuse through tissue. This makes it virtually impossible to infect the majority of tumor cells in vivo and results in inadequate gene transfer. This problem can be addressed by allowing limited viral replication. Limited viral replication facilitates greater penetration of virions into tissue and can improve gene transfer. We have developed a strategy of limited viral replication using AdRSVlaclys, a chemically modified E1-deleted adenovirus, to codeliver an exogenous plasmid encoding the adenovirus E1 region. This system allows one round of viral replication. We examined the effect of this limited adenovirus replication in vitro and in vivo. In culture, codelivery of virus and pE1 resulted in a large increase in infected cells when compared with control cells exposed to virus and pUC19. In experiments on nude mice bearing HeLa ascites tumors, intraperitoneal injection of AdRSVlaclys/pE1 resulted in a significantly higher percentage of infected HeLa cells as compared with the PBS controls (p < 0.05) or the AdRSVlaclys/pUC19 controls (p < 0.01). These data demonstrate that the transcomplementation of replication-deficient adenovirus with exogenous E1 DNA leads to limited replication, and this controlled replication enhances gene transfer efficiency of adenovirus in vivo.
Adenoviridae↗
Transcription of Epstein-Barr virus latent cycle genes in oral hairy leukoplakia.
The hairy leukoplakia lesion (HLP) is a unique example of a permissive infection with Epstein-Barr virus (EBV) in the tongue epithelium. HLP contains abundant replicating viral DNA and may be coinfected with multiple EBV strains. In this study, characterization of viral gene transcription within HLP biopsy specimens revealed that several genes, usually expressed in latently infected lymphocytes, are also transcribed in the HLP lesion. The BamHI W and C promoters, (Wp and Cp) are consistently active in the HLP lesion, resulting in transcription and processing of mRNAs that encode the Epstein-Barr nuclear antigens (EBNAs) EBNA-LP, EBNA1, EBNA2, EBNA3B, and EBNA3C. The EBNA2 protein has been shown to activate expression of the EBV receptor, CD21. In HLP, CD21 transcription is also detected, usually in samples that contain transcripts for EBNA2. Transcripts encoding the LMP1 gene, the LMP2 gene, and rightward transcripts from the BamHI A fragment of the EBV genome are also detected in HLP. These gene products are invariably expressed in latently infected lymphocytes. This pattern of transcription suggests that genes characteristic of latent infection are also expressed in HLP. The activation of Wp and expression of EBNA2 and CD21 may contribute to the unique ability of the HLP lesion to permit superinfection and viral replication of multiple EBV strains.
Cell Line↗
The development of conditionally replicative adenoviruses for cancer therapy.
Replicative viral agents represent a novel approach for treating neoplastic disease. Tumor cell killing by the viral agent is achieved by direct consequence of the viral replication. Relative sparing of nontumor is, however, required to provide a therapeutic index of utility for cancer treatment. To this end, an ideal viral agent would, thus, possess several logical attributes, including stability and efficiency for infection and lateral spread in vivo, a preference for replication in tumor versus nontumor cells, and the capability of avoiding early detection-and eradication-by the immune system. To date, none of the agents has exhibited optimal characteristics with regard to the aforementioned attributes. Adenovirus, however, has lent itself to a process of extensive engineering that is dealing with each and every one of the major requirements and that is realizing its clinical potential. An advanced understanding of the cancer phenotype, as well as achievements in functionally exploiting viral plasticity, predicate the design and realization of conditionally replicative adenoviral agents with improved characteristics for cancer therapy.
Adenoviridae↗
Modulation of HIV-enhancer activity by heterologous agents: a minireview.
The enhancer region of the human immunodeficiency virus (HIV) long terminal repeat (LTR) contains two 10-bp (5'-GGGACTTTCC) repeats (core enhancers) which constitute the binding sites for the ubiquitous inducible cellular transcription factor, NF-kappa B. The NF-kappa B motifs of the LTR play a central role in transcriptional activation of the LTR by several heterologous viral proteins and various external chemical and physical stimuli. Activation of the HIV enhancer by these agents may lead to the onset of HIV gene expression resulting in active viral replication. Viral genes and chemical agents, which interfere with the activity of the enhancers may be useful in inhibiting HIV gene expression, thereby suppressing HIV replication.
Base Sequence↗