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At least 325 records · Page 18Linked to original sources
PubMed2005

Splicing of rhesus rhadinovirus R15 and ORF74 bicistronic transcripts during lytic infection and analysis of effects on production of vCD200 and vGPCR.

Rhesus macaque rhadinovirus (RRV) is the rhesus macaque homologue of human herpesvirus 8 (HHV-8). Here we examine expression of RRV R15 and ORF74, homologues of K14 and ORF74 of HHV-8, respectively. As in HHV-8, transcripts encoding RRV R15 and ORF74 are bicistronic. However, unlike what has been suggested for HHV-8, RRV R15- and ORF74-encoding transcripts are expressed late during lytic infection and undergo unique splicing events that result in the production of transcripts capable of encoding vGPCR, as well as membrane-associated and secreted forms of vCD200. The alternative splicing for vCD200 has implications for viral pathogenesis.

Blotting, Northern↗
PubMed2006

Elevated PrPC expression predisposes to increased HSV-1 pathogenicity.

PrPC is a ubiquitously expressed glycophos-phatidylinositol-linked cell-surface glycoprotein found primarily in neural tissue. Although its normal function has not been established, there is evidence suggesting that PrPC is involved in cell signalling and cellular homeostasis. This suggests that variation in neuronal expression levels of this protein contributes towards pathogenicity induced by neurotropic agents. We have investigated the pathological response to infection with herpes simplex virus type-1 (HSV-1) in strains of mice that express different levels of PrPC. Prnp-/- mice fail to express PrPC due to an interruption in the open reading frame of the Prnp gene, whilst tg19 and tga20 mice express approximately 5 and 10 times more PrPC protein, respectively, than wild-type animals. Mice that express normal or increased levels of PrPC protein were more susceptible to acute HSV-1 infection than Prnp-/- mice. Following ear pinna inoculation with HSV-1 SC16, the order of susceptibility was tga20>tg19>wild-type>Prnp-/-. This trend was reversed when latent virus was assessed. Prnp-/- mice expressed significantly higher levels of latency-associated transcript-positive neurons in various tissues when compared with wild-type, tg19 and tga20 mice. Collectively, our data show that acute HSV-1 replication proceeds more efficiently in neuronal tissue that expresses PrPC protein and lends support to the view that this protein is involved in regulation of neurotropic viral pathogenesis. This suggests that interference of PrPC expression, or possible biochemical pathways associated with its function, may serve as an effective means of limiting the pathogenesis of acute HSV-1 infection.

Animals↗
PubMed1993

Defective T cell receptor-mediated signaling and differential induction of T cell functions by murine AIDS virus superantigen.

A B cell line, B6-1710, expressing murine AIDS virus superantigen stimulates T cell hybridomas derived from a Ld-specific CTL clone to produce IL-2 regardless of their CD4/CD8 phenotype. However, B6-1710 cell did not stimulate the original CTL clone, L3, in either proliferation or cytolytic assays. Both B6-1710 and Ld+ P815 cells stimulated a significant Ca2+ influx in the T cell hybridomas. In contrast, only P815 stimulated tyrosine phosphorylation of a 19-kDa protein in the T cell hybridoma. The addition of the nonspecific protein kinase C activator PMA restored the proliferative response of L3 cells to B6-1710. PMA did not induce the lysis of B6-1710 cells by L3. These results suggest that murine AIDS virus encoded superantigen elicits a TCR-mediated signal different from that caused by nominal Ag. This different signaling by viral superantigen may be important for the development of viral pathogenesis in vivo.

Animals↗
PubMed1997

Current status of respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) vaccine development: memorandum from a joint WHO/NIAID meeting.

A Joint WHO/National Institute of Allergy and Infectious Diseases (NIAID) meeting on the current status of respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) vaccine development was held in Bethesda, MD, from 30 September to 1 October 1996. The meeting summarized the worldwide impact of RSV and PIV3; presented the current status of development of RSV and PIV3 vaccines; and examined the applications of recombinant DNA technology to the development and characterization of vaccines and to the understanding of viral pathogenesis.

Adult↗
PubMed2001

Mutagenesis of the varicella-zoster virus genome: lessons learned.

The varicella-zoster virus (VZV) genome encodes at least 70 genes. We have developed a cosmid based system to inactivate individual viral genes or to insert foreign genes into the genome. We have shown that many VZV genes are not required for replication of the virus in cell culture. Several of these genes, including VZV ORF61, ORF47, and ORF10, have unexpected phenotypes in cell culture and differ from their homologs in the better studied herpes simplex virus (HSV). We have also used the Oka strain of VZV as a live virus vaccine vector. Guinea pigs vaccinated with recombinant VZV expressing HSV-2 glycoprotein D and challenged with HSV-2 have reduced severity of primary genital herpes and reduced mortality compared to animals receiving parental VZV. Recently we have inserted the human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) glycoprotein 160 genes into the Oka strain of VZV and have shown that these proteins are expressed in recombinant virus-infected cells. Thus, directed mutagenesis of the VZV genome is providing new insights into viral pathogenesis and may provide new candidate vaccines.

Animals↗
PubMed2001

Anti-HIV agent MAP30 modulates the expression profile of viral and cellular genes for proliferation and apoptosis in AIDS-related lymphoma cells infected with Kaposi's sarcoma-associated virus.

The anti-HIV agent MAP30 (Momordica anti-HIV protein, 30 kDa) inhibits the proliferation of BC-2, an AIDS-related primary effusion lymphoma (PEL) cell line derived from an AIDS patient. BC-2 cells are latently infected with Kaposi's sarcoma-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV8). We examined the effect of MAP30 on the expression of viral and cellular genes in BC-2 during latent and lytic states of the viral life cycle. By Northern analysis and RT-PCR, we found that MAP30 downregulates the expression of viral cyclin D (vCD), viral interleukin-6 (vIL-6), and viral FLIP (vFLIP), genes involved in cell cycle regulation, viral pathogenesis, and apoptosis. By pathway-specific cDNA microarray analysis, we found that BC-2 cells express high levels of egr-1, ATF-2, hsp27, hsp90, IkappaB, mdm2, skp1, and IL-2, cellular genes involved in mitogenesis, tumorigenesis, and inhibition of apoptosis in NFkappaB and p53 signaling pathways. These results define for the first time the specific cellular pathways involved in AIDS-related tumorigenesis and suggest specific novel targets for the treatment. Furthermore, we found that MAP30 downregulates the expression of egr-1, ATF-2, hsp27, hsp90, IkappaB, mdm2, and Skp1, while it upregulates the pro-apoptotic-related genes Bax, CRADD, and caspase-3. Thus, MAP30 modulates the expression of both viral and cellular genes involved in KS pathogenesis. These results provide valuable insight into the molecular mechanisms of MAP30 anti-KS action and suggest its utility as a therapeutic agent against AIDS-related tumors.

Anti-HIV Agents↗
PubMed2006

Human cytomegalovirus (HCMV) infection of endothelial cells promotes naive monocyte extravasation and transfer of productive virus to enhance hematogenous dissemination of HCMV.

Human cytomegalovirus (HCMV) pathogenesis is dependent on the hematogenous spread of the virus to host tissue. While data suggest that infected monocytes are required for viral dissemination from the blood to the host organs, infected endothelial cells are also thought to contribute to this key step in viral pathogenesis. We show here that HCMV infection of endothelial cells increased the recruitment and transendothelial migration of monocytes. Infection of endothelial cells promoted the increased surface expression of cell adhesion molecules (intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and platelet endothelial cell adhesion molecule 1), which were necessary for the recruitment of naïve monocytes to the apical surface of the endothelium and for the migration of these monocytes through the endothelial cell layer. As a mechanism to account for the increased monocyte migration, we showed that HCMV infection of endothelial cells increased the permeability of the endothelium. The cellular changes contributing to the increased permeability and increased naïve monocyte transendothelial migration include the disruption of actin stress fiber formation and the decreased expression of lateral junction proteins (occludin and vascular endothelial cadherin). Finally, we showed that the migrating monocytes were productively infected with the virus, documenting that the virus was transferred to the migrating monocyte during passage through the lateral junctions. Together, our results provide evidence for an active role of the infected endothelium in HCMV dissemination and pathogenesis.

Cell Differentiation↗
PubMed2006

Live-cell characterization and analysis of a clinical isolate of bovine respiratory syncytial virus, using molecular beacons.

Understanding viral pathogenesis is critical for prevention of outbreaks, development of antiviral drugs, and biodefense. Here, we utilize molecular beacons to directly detect the viral genome and characterize a clinical isolate of bovine respiratory syncytial virus (bRSV) in living cells. Molecular beacons are dual-labeled, hairpin oligonucleotide probes with a reporter fluorophore at one end and a quencher at the other; they are designed to fluoresce only when hybridizing to a complementary target. By imaging the fluorescence signal of molecular beacons, the spread of bRSV was monitored for 7 days with a signal-to-noise ratio of 50 to 200, and the measured time course of infection was quantified with a mathematical model for viral growth. We found that molecular beacon signal could be detected in single living cells infected with a viral titer of 2 x 10(3.6) 50% tissue culture infective doses/ml diluted 1,000 fold, demonstrating high detection sensitivity. Low background in uninfected cells and simultaneous staining of fixed cells with molecular beacons and antibodies showed high detection specificity. Furthermore, using confocal microscopy to image the viral genome in live, infected cells, we observed a connected, highly three-dimensional, amorphous inclusion body structure not seen in fixed cells. Taken together, the use of molecular beacons for active virus imaging provides a powerful tool for rapid viral infection detection, the characterization of RNA viruses, and the design of new antiviral drugs.

Animals↗
PubMed2005

Molecular biology of pseudorabies virus: impact on neurovirology and veterinary medicine.

Pseudorabies virus (PRV) is a herpesvirus of swine, a member of the Alphaherpesvirinae subfamily, and the etiological agent of Aujeszky's disease. This review describes the contributions of PRV research to herpesvirus biology, neurobiology, and viral pathogenesis by focusing on (i) the molecular biology of PRV, (ii) model systems to study PRV pathogenesis and neurovirulence, (iii) PRV transsynaptic tracing of neuronal circuits, and (iv) veterinary aspects of pseudorabies disease. The structure of the enveloped infectious particle, the content of the viral DNA genome, and a step-by-step overview of the viral replication cycle are presented. PRV infection is initiated by binding to cellular receptors to allow penetration into the cell. After reaching the nucleus, the viral genome directs a regulated gene expression cascade that culminates with viral DNA replication and production of new virion constituents. Finally, progeny virions self-assemble and exit the host cells. Animal models and neuronal culture systems developed for the study of PRV pathogenesis and neurovirulence are discussed. PRV serves asa self-perpetuating transsynaptic tracer of neuronal circuitry, and we detail the original studies of PRV circuitry mapping, the biology underlying this application, and the development of the next generation of tracer viruses. The basic veterinary aspects of pseudorabies management and disease in swine are discussed. PRV infection progresses from acute infection of the respiratory epithelium to latent infection in the peripheral nervous system. Sporadic reactivation from latency can transmit PRV to new hosts. The successful management of PRV disease has relied on vaccination, prevention, and testing.

Animals↗
PubMed2006

A circadian model for viral persistence.

Persistently infecting DNA viruses depend heavily on host cell DNA synthesis machinery. Replication of cellular and viral DNA is inhibited by mutagenic stress. It is hypothesized that diurnal regulation of viral DNA replication may occur at the level of cell cycle checkpoints and DNA repair, to protect DNA from exposure to UV light or other mutagens. This highly conserved mechanism is traced back to viruses that persist in prokaryotes and eukaryotes. Inhibition of viral DNA replication and the cell cycle in response to UV light may represent a functional building block in the evolution of circadian-gated DNA replication. Viral DNA replication appears to be closely linked to the circadian clock by interaction of viral promoters, early viral proteins and transcription factors. It is proposed here that under certain conditions viral oncogene expression is phase-shifted relative to that of tumor suppressor and DNA repair genes. The resulting desynchrony of checkpoint controls and DNA repair from diurnal genotoxic exposure produces cyclic periods of suboptimal response to DNA damage. This temporal vulnerability to genotoxic stress produces a "mutator phenotype" with inherent genome instability. The proposed model delineates areas of research with implications for viral pathogenesis and therapeutics.

Cell Cycle↗
PubMed1990

Differential interaction of virulent and attenuated influenza virus strains with ferret alveolar macrophages: possible role in pathogenicity.

The ferret provides a unique model for the study of human influenza. The interaction between alveolar macrophages and virus strains with different levels of virulence was examined in vitro. The greater virulence of wild-type A strains over type B and C viruses was reflected in the higher production of infectious virus progeny and subsequent cytopathology, even though the expression of viral antigens was equivalent for all strains tested. These included A/Ann Arbor/6/60 (H2N2) and A/Rochester/1/82 (H3N2), B/Hong Kong/72, and C/Ann Arbor/1/50. The attenuated cold-adapted and temperature-sensitive variant of A/Ann Arbor/6/60 behaved like its parent except that a longer period was needed to reach peak viral release. In contrast, the avirulent host-range reassortant CR-43-3 did not productively replicate, though viral antigen expression was comparable to that of the other strains. Type C virus infected few cells and these continued to release low virus levels in the absence of detectable cytopathology. The results suggest that the ability of certain strains to infect and replicate in alveolar macrophages can be correlated to their in vivo virulence and may play a role in determining the course of viral pathogenesis.

Animals↗
PubMed1999

Variants from the diverse virus population identified at seroconversion of a clade A human immunodeficiency virus type 1-infected woman have distinct biological properties.

Development of effective therapeutics to prevent new infections with human immunodeficiency type 1 (HIV-1) is predicated on an understanding of the properties that provide a selective advantage to a transmitted viral population. In contrast to the homogeneous virus population that typifies early HIV-1 infection of men, the viral population in women recently infected with clade A HIV-1 is genetically diverse, based on evaluation of the envelope gene. A longitudinal study of viral envelope evolution in several women suggested that representative envelope variants detected at seroconversion had distinct biological properties that affected viral fitness. To test this hypothesis, a full-length, infectious molecular clone, Q23-17, was obtained from an infected woman 1 year following seroconversion, and chimeric viruses containing envelope genes representative of seroconversion and 27-month-postseroconversion populations were constructed. Dendritic cells (DC) could transfer infection of seroconversion variant Q23ScA, which dominated the viral population in the year following seroconversion, and the closely related 1-year isolate Q23-17 to resting peripheral blood mononuclear cells (PBMC). In contrast, resting PBMC exposed to DC pulsed with Q23ScB, which was detected infrequently in samples after seroconversion, or the 27-month chimeras were inconsistently infected. Additionally, quiescent PBMC infected with Q23ScA or Q23-17 proliferated more robustly than uninfected cells or cells infected with the other envelope chimeras in response to immobilized anti-CD3. Stimulation with tetanus toxoid led to an increased proportion of CD45RA+ cells and a decreased expression of CD28 on CD45RO+ cells in cultures of Q23-17-infected PBMC. These data demonstrate that variants from the heterogeneous seroconversion clade A HIV-1 population in a Kenyan woman have distinct biological features that may influence viral pathogenesis.

Amino Acid Sequence↗
PubMed1999

Resistance of interleukin-1beta-deficient mice to fatal Sindbis virus encephalitis.

Interleukin-1beta (IL-1beta) concentrations are frequently elevated in central nervous system (CNS) viral infections, but the pathophysiologic significance of such elevations is not known. To examine the role of IL-1beta in CNS viral pathogenesis, we compared the natural histories of IL-1beta-deficient and wild-type 129 SV(ev) mice infected with a neurovirulent viral strain, neuroadapted Sindbis virus (NSV). We found that the incidence of severe paralysis and death was markedly decreased in NSV-infected IL-1beta-/- mice compared to NSV-infected wild-type mice (4 versus 88%, P < 0.001). Despite this marked difference in clinical outcome, no differences in numbers of apoptotic cells or presence of histopathologic lesions in the brains of moribund wild-type mice and those of clinically healthy IL-1beta-/- mice could be detected. These results suggest that IL-1beta deficiency is protective against fatal Sindbis virus infection by a mechanism that does not involve resistance to CNS virus-induced apoptosis or histopathology.

Alphavirus Infections↗
PubMed1999

Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs.

Infection of macaques with chimeric simian-human immunodeficiency virus (SHIV) provides an excellent in vivo model for examining the influence of envelope on HIV-1 pathogenesis. Infection with a pathogenic CCR5 (R5)-specific enveloped virus, SHIVSF162P, was compared with infection with the CXCR4 (X4)-specific SHIVSF33A.2. Despite comparable levels of viral replication, animals infected with the R5 and X4 SHIV had distinct pathogenic outcomes. SHIVSF162P caused a dramatic loss of CD4+ intestinal T cells followed by a gradual depletion in peripheral CD4+ T cells, whereas infection with SHIVSF33A.2 caused a profound loss in peripheral T cells that was not paralleled in the intestine. These results suggest a critical role of co-receptor utilization in viral pathogenesis and provide a reliable in vivo model for preclinical examination of HIV-1 vaccines and therapeutic agents in the context of the HIV-1 envelope protein.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Viruses as quasispecies: biological implications.

During viral infections, the complex and dynamic distributions of variants, termed viral quasispecies, play a key role in the adaptability of viruses to changing environments and the fate of the population as a whole. Mutant spectra are continuously and avoidably generated during RNA genome replication, and they are not just a by-product of error-prone replication, devoid of biological relevance. On the contrary, current evidence indicates that mutant spectra contribute to viral pathogenesis, can modulate the expression of phenotypic traits by subpopulations of viruses, can include memory genomes that reflect the past evolutionary history of the viral lineage, and, furthermore, can participate in viral extinction through lethal mutagenesis. Also, mutant spectra are the target on which selection and random drift act to shape the long-term evolution of viruses. The biological relevance of mutant spectra is the central topic of this chapter.

Evolution, Molecular↗
PubMed2006

Quantitative analysis of Kaposi sarcoma-associated herpesvirus (KSHV) in KSHV-associated diseases.

BACKGROUND: Accurate numbers of copies of Kaposi sarcoma-associated herpesvirus (KSHV) and numbers of virus-infected cells in lesions caused by KSHV-associated diseases are unknown. METHODS: Quantitative polymerase chain reaction (PCR) and computerized imaging of immunohistochemical analysis were performed on pathologic sections of samples from persons with KSHV-associated diseases. RESULTS: Real-time PCR and semiquantitative PCR-Southern blotting demonstrated that DNA extracted from biopsy samples of KS lesions contained approximately 1-2 viral copies/cell. KSHV-associated lymphoma contained 10-50 viral copies/cell. Computerized-image analysis demonstrated that approximately 49% of cells expressed KSHV-encoded latency-associated nuclear antigen in KS biopsy samples. On the basis of results of real-time PCR and computerized-image analysis, the predicted number of viral copies was 3.2 viral copies/cell in KS lesions. Computerized-image analysis also revealed that the expression of open-reading frame (ORF)-50 protein, an immediate early protein of KSHV, was very rare in KS lesions, which implies that they were mainly composed of proliferating cells latently infected with KSHV. In multicentric Castleman disease lesions, 25% of virus-infected cells expressed ORF50 protein, which suggests the frequent lytic replication of KSHV. CONCLUSIONS: Numbers of viral copies and of virus-positive cells vary among KSHV-associated diseases, which suggests different mechanisms of viral pathogenesis. The combination of real-time PCR and computerized-image analysis provides a useful tool for the assessment of the number of viral copies in KSHV-associated diseases.

Herpesviridae Infections↗
PubMed1993

The application of quantitative polymerase chain reaction to therapeutic monitoring.

UNLABELLED: Use of polymerase chain reaction in HIV monitoring: The polymerase chain reaction can be used not only to detect the presence of viral sequences but also to provide a semiquantitative or a precise evaluation of the number of copies of genome present. Integral to the development of accurate and reproducible assays have been critical advances in polymerase chain reaction technology. In addition, standardization of protocols and reagents has proved invaluable. The HIV life cycle permits both DNA and RNA to be targeted. Although early cross-sectional studies provided little insight into disease progression, recent longitudinal studies have provided valuable information on HIV infection. CONCLUSION: A rapid and simple quantitative assay for HIV RNA in plasma or sera has been developed that should prove valuable in determining the natural history of infection, dissecting viral pathogenesis and monitoring the efficacy of therapeutic intervention.

Binding, Competitive↗
PubMed1979

Immunoperoxidase staining for detection of Colorado tick fever virus, and a study of congenital infection in the mouse.

Indirect immunoperoxidase (IP) staining was evaluated for sensitivity and specificity in detecting Colorado tick fever (CTF) virus antigen in infected cell cultures and infected mouse tissues, and then was applied to a study of congenital CTF infection in mice. The sensitivity of IP staining was comparable to that of immunofluorescence staining in detecting CTF antigen in infected cell cultures. Endogenous peroxidase activity of mouse tissues caused nonspecific reactivity in the IP system, but this could be abolished by treatment with sodium azide and hydrogen peroxide without destroying CTF antigen. Offspring of mice infected with CTF virus during the 2nd week of pregnancy showed a highly significant increase in the incidence of stillbirths and neonatal deaths as compared with offspring of uninfected controls. CTF antigen or virus was demonstrable in only a low proportion (7%) of embryos, ill newborns or stillborns examined, but a high proportion of mice examined at a time when maternal antibody would be lost (6 and 12 weeks) showed CTF antibody, indicating a higher incidence of infection. IP staining showed potential for use in studies of viral pathogenesis in the mouse model.

Animals↗