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PubMed2005

Proceedings of the fourth National Congress of the Italian Society of Virology.

The aim of the yearly National Congress of the Italian Society of Virology (SIV) is to promote the discussion between senior and younger researchers to improve the knowledge and scientific collaboration among the various areas of Virology. The invited and selected lecturers of the fourth National Congress of SIV covered the following topics: general Virology and viral Genetics; virus host interactions and pathogenesis; viral immunology and vaccines; emerging and re-emerging viral diseases; antiviral therapy; innovative diagnostics; viral biotechnologies and gene therapy. As in the previous edition (Salata and Palù, 2004 J Cell Physiol 199:171-173), a specific topic was thoroughly covered in a roundtable. In this edition the overviewed topic was HCV, from epidemiology and genetic variability to immunology and antiviral therapy. The final program can be found at the web site http://www.siv-virologia.it. A summary of the oral presentations of the 2004 meeting is reported.

Biotechnology↗
PubMed1988

Structure, function, and intracellular processing of paramyxovirus membrane proteins.

Paramyxoviruses are a fascinating group of viruses with diverse hosts and disease manifestations. They are valuable systems for studying viral pathogenesis, molecular mechanisms of negative strand viral replication, and glycoprotein structure and function. In the past few years this group of viruses has received increased attention and as a result there is a wealth of new information. For example, most of the genes of many paramyxoviruses have been cloned and sequenced. The recent availability of sequence information from a number of paramyxoviruses now allows the direct comparison of the amino acid sequence and determinants of secondary structure of analogous genes across the family of viruses. Such comparisons are revealing for two reasons. First, results provide clues to the evolution of these viruses. Second, and more importantly, comparisons of analogous genes may point to sequences and structural determinants that are central to the function of the individual proteins. Below is a comparison of five of the paramyxovirus genes with a discussion of the implications of common structural determinants for function, intracellular processing, and evolutionary origin. The focus is on the paramyxovirus membrane proteins, although other proteins are discussed briefly.

Amino Acid Sequence↗
PubMed2005

Human metapneumovirus: a ubiquitous and long-standing respiratory pathogen.

BACKGROUND: Human metapneumovirus (hMPV) is a recently described human pathogen first identified in respiratory specimens of young children suffering from respiratory syndromes ranging from mild to severe. METHODS AND RESULTS: Virological studies have reported the presence of hMPV infections in many countries from all continents. Seroprevalence studies have indicated that the virus has been circulating in humans for more than 50 years and that it infects virtually all children by the ages of 5-10 years. In young children, hMPV has been mainly associated with bronchiolitis but also with pneumonitis, otitis media and acute exacerbation of asthma. The contribution of hMPV in respiratory syndromes of adults has been studied considerably less; initial studies have indicated a role for this pathogen in flu-like syndromes and in significant percentages of chronic obstructive pulmonary disease exacerbations and cases of community-acquired pneumonia during the winter-spring period. Both primate and rodent experimental models have been used to characterize the pathogenesis of this respiratory virus. In some of these models, intranasal hMPV inoculation has elicited not only important viral replication but also significant pulmonary inflammation and clinical disease. Recently a few groups have developed reverse genetic systems for hMPV, allowing a better understanding of viral pathogenesis and generation of attenuated viral strains for immunization. CONCLUSIONS: Recent studies on hMPV have provided a better understanding of the epidemiology and pathogenesis associated with this viral infection, and have enhanced the prospect of developing efficient therapeutic agents and vaccine candidates.

Animals↗
PubMed1999

Pathogenesis of chimeric MHV4/MHV-A59 recombinant viruses: the murine coronavirus spike protein is a major determinant of neurovirulence.

The mouse hepatitis virus (MHV) spike glycoprotein, S, has been implicated as a major determinant of viral pathogenesis. In the absence of a full-length molecular clone, however, it has been difficult to address the role of individual viral genes in pathogenesis. By using targeted RNA recombination to introduce the S gene of MHV4, a highly neurovirulent strain, into the genome of MHV-A59, a mildly neurovirulent strain, we have been able to directly address the role of the S gene in neurovirulence. In cell culture, the recombinants containing the MHV4 S gene, S4R22 and S4R21, exhibited a small-plaque phenotype and replicated to low levels, similar to wild-type MHV4. Intracranial inoculation of C57BL/6 mice with S4R22 and S4R21 revealed a marked alteration in pathogenesis. Relative to wild-type control recombinant viruses (wtR13 and wtR9), containing the MHV-A59 S gene, the MHV4 S gene recombinants exhibited a dramatic increase in virulence and an increase in both viral antigen staining and inflammation in the central nervous system. There was not, however, an increase in the level of viral replication in the brain. These studies demonstrate that the MHV4 S gene alone is sufficient to confer a highly neurovirulent phenotype to a recombinant virus deriving the remainder of its genome from a mildly neurovirulent virus, MHV-A59. This definitively confirms previous findings, suggesting that the spike is a major determinant of pathogenesis.

Animals↗
PubMed1974

Pathogenesis of temperature-sensitive mutants of sindbis virus in the embryonated egg. I. Characterization and kinetics of viral multiplication.

Exploratory experiments were performed with temperature-sensitive (ts) mutants of Sindbis virus for studies on viral pathogenesis in the embryonated egg, a host which is immunologically underdeveloped. Parent and mutants were found to be virulent at the permissive temperature (33 C), but only the mutants were attenuated at the nonpermissive temperature (38.5 C). The degree of attenuation varied with the mutant and the route of inoculation. Chicks which survived infection by ts mutants at a nonpermissive temperature weighed the same as controls and showed no obvious abnormalities on gross examination. Whenever death of the embryo at the nonpermissive temperature occurred after inoculation with a mutant, it was apparently due to the selection of a population of temperature-insensitive virulent revertants. Kinetic studies showed that, after inoculation of the chorioallantoic membrane and incubation at the permissive temperature, a number of cycles of virus multiplication and dissemination apparently occurred rapidly. At the nonpermissive temperature, multiplication was undetectable. Certain pathophysiological signs were seen in the slower, less virulent infections by the mutants at the permissive temperature that were apparently masked or obscured in the more virulent, rapid infection by the parent. From these results and those reported in a subsequent paper, it appears that ts mutants of viruses possess potential as valuable tools for analyzing pathogenesis and immunity in the intact animal host that are complementary to more conventional approaches which employ normal (temperature-insensitive) viruses.

Animals↗
PubMed2006

Highlights from the 5th Annual Meeting of the Italian Society of Virology.

The 5th National Congress of the Italian Society of Virology (SIV) was attended by junior- and senior-level virologists to promote interactions and scientific collaborations among the different areas of Virology and allied sciences. The invited and selected lecturers covered the following topics: General Virology and Viral Genetics; Virus-host Interaction and Pathogenesis; Viral Oncogenesis; Viral Immunology and Vaccines; Anti-viral Therapy; Innovative Diagnostics; Viral Biotechnologies and Cell and Gene Therapy. As in the previous editions (Salata and Palù, 2004; Salata et al., 2005), a specific topic was thoroughly covered in a roundtable. This year the elected subject was "HIV: determinants of pathogenicity and clinical implications." The final program and the abstract book can be found at the web site http://www.siv-virologia.it. This report summarizes the lessons learned from the plenary lectures and the selected oral presentations of the 2005 meeting.

Humans↗
PubMed2004

The vaccinia virus B1R kinase induces p53 downregulation by an Mdm2-dependent mechanism.

Poxvirus infection has a strong effect on cellular functions. To understand viral pathogenesis, it is necessary to know how viral proteins interact with host proteins. The B1R kinase is an early viral gene required for vaccinia virus DNA synthesis and replication, but no cellular substrate is known for this viral kinase. B1R is able to hyperphosphorylate p53 in several residues in the N-terminal transactivation domain, including Ser15 and Thr18. B1R does not phosphorylate Mdm2. B1R promotes an increase in p53 ubiquitination and a reduction of p53 acetylation by p300. The over-expressed B1R protein induces the degradation of p53 in a concentration-dependent manner and is lost when Ser15 and Th18 are changed to alanine or when the B1R kinase is inactivated by introducing the K149Q substitution. The B1R-induced downregulation of p53 requires Mdm2. The hyperphosphorylated p53 is transcriptionally active, and this activity also falls as B1R increases. The BAX gene promoter is more sensitive to this reduction of transcription than p21 or 14-3-3 gene promoters. This effect of B1R on p53 can be one of the mechanisms by which vaccinia virus exerts its role in infected cells.

Alanine↗
PubMed2003

Viral mimicry of cytokines, chemokines and their receptors.

Viruses have evolved elegant mechanisms to evade detection and destruction by the host immune system. One of the evasion strategies that have been adopted by large DNA viruses is to encode homologues of cytokines, chemokines and their receptors--molecules that have a crucial role in control of the immune response. Viruses have captured host genes or evolved genes to target specific immune pathways, and so viral genomes can be regarded as repositories of important information about immune processes, offering us a viral view of the host immune system. The study of viral immunomodulatory proteins might help us to uncover new human genes that control immunity, and their characterization will increase our understanding of not only viral pathogenesis, but also normal immune mechanisms. Moreover, viral proteins indicate strategies of immune modulation that might have therapeutic potential.

Chemokines↗
PubMed1995

Molecular biologic and pathogenetic analysis of hepatitis delta virus.

Hepatitis delta virus (HDV) consists of an envelope derived from hepatitis B virus (HBV) and a nucleocapsid consisting of hepatitis delta antigen and a circular RNA genome. Both the delta antigen and the RNA possess many unique properties which play crucial roles in the life cycle of HDV. They may also contribute indirectly to the mechanism of viral pathogenesis.

Antigens, Viral↗
PubMed2004

Role of viral vectors and virion shells in cellular gene expression.

The role of the virion shell in viral pathogenesis is relatively unknown yet the use of viral vectors in human gene transfer experiments requires an understanding of these interactions. In this study, we used DNA microarrays to identify genes modulated during pathogenic adenovirus or nonpathogenic adeno-associated virus infections. Responses to wt viruses, recombinant vectors, or empty virion particles were compared. Adeno-associated virus shells induced nearly the full complement of changes elicited by the intact virus. The cellular genes elicited a nonpathogenic response, with antiproliferative genes being induced as a cluster. In contrast, adenovirus and adenovirus empty capsid infection yielded a broader response and subset, respectively, including induction of immune and stress-response genes associated with pathogenic effects. Our studies show that the impact of the viral capsid on cellular gene expression, and potential host toxicity, must be considered independent of the vector genome for safe gene transfer in the clinic.

Adenoviridae↗
PubMed2000

Viral mechanisms of immune evasion.

During the millions of years they have coexisted with their hosts, viruses have learned how to manipulate host immune control mechanisms. Viral gene functions provide an overview of many relevant principles in cell biology and immunology. Our knowledge of viral gene functions must be integrated into virus-host interaction networks to understand viral pathogenesis, and could lead to new anti-viral strategies and the ability to exploit viral functions as tools in medicine.

Animals↗
PubMed2000

Viral mechanisms of immune evasion.

During the millions of years they have coexisted with their hosts, viruses have learned how to manipulate host immune control mechanisms. Viral gene functions provide an overview of many relevant principles in cell biology and immunology. Our knowledge of viral gene functions must be integrated into virus-host interaction networks to understand viral pathogenesis, and could lead to new anti-viral strategies and the ability to exploit viral functions as tools in medicine.

Antibody Formation↗
PubMed2000

Viral mechanisms of immune evasion.

During the millions of years they have coexisted with their hosts, viruses have learned how to manipulate host immune control mechanisms. Viral gene functions provide an overview of many relevant principles in cell biology and immunology. Our knowledge of viral gene functions must be integrated into virus-host interaction networks to understand viral pathogenesis, and could lead to new anti-viral strategies and the ability to exploit viral functions as tools in medicine.

Animals↗
PubMed2000

Yeast perspectives on HIV-1 VPR.

Increasing evidence suggests that HIV-1 viral protein R (Vpr) plays an important role in viral pathogenesis, as its functions are being linked to viral activation, suppression of human immune functions and depletion of human CD4 lymphocytes, which are the major clinical manifestation of AIDS. In vitro, Vpr shows multiple activities both in mammalian and yeast cells, which include nuclear transport, induction of cell cycle G2 arrest, morphological changes and cell death. The occurrence of these activities in yeast indicates that Vpr interacts with highly conserved cellular processes to cause these effects and allows Vpr activities to be studied in these genetically well characterized organisms. Studies of Vpr in fission yeast (Schizosaccharomyces pombe) and budding yeast (Saccharomyces cerevisiae) have helped to establish these major conclusions. 1) Vpr induces G2 arrest through inhibitory phosphorylation of the cyclin-dependent kinase by a pathway in which protein phosphatase 2A plays an important role. 2) Vpr fulfills its essential role in the nuclear transport of the viral pre-integration complex by binding to a novel site on importin ?. 3) Vpr induces apoptosis by directly permeabilizing the mitochondrial membrane. 4) Vpr also appears to kill cells by mitochondrial-independent mechanisms. 5) G2 arrest and cell death induced by Vpr are two independent functions, and 6) amino acid residues of Vpr at position 29, 33 and 71 are important sites for maintaining the overall structure of Vpr. Future studies of Vpr in yeast are expected to make additional contributions to understanding the mechanisms of Vpr activities and may also help address the importance of these activities during the course of a HIV-1 infection.

Apoptosis↗
PubMed2005

Remote site control of an active site fidelity checkpoint in a viral RNA-dependent RNA polymerase.

The kinetic, thermodynamic, and structural basis for fidelity of nucleic acid polymerases remains controversial. An understanding of viral RNA-dependent RNA polymerase (RdRp) fidelity has become a topic of considerable interest as a result of recent experiments that show that a 2-fold increase in fidelity attenuates viral pathogenesis and a 2-fold decrease in fidelity reduces viral fitness. Here we show that a conformational change step preceding phosphoryl transfer is a key fidelity checkpoint for the poliovirus RdRp (3Dpol). We provide evidence that this conformational change step is orientation of the triphosphate into a conformation suitable for catalysis, suggesting a kinetic and structural model for RdRp fidelity that can be extrapolated to other classes of nucleic acid polymerases. Finally, we show that a site remote from the catalytic center can control this checkpoint, which occurs at the active site. Importantly, similar connections between a remote site and the active site exist in a wide variety of viral RdRps. The capacity for sites remote from the catalytic center to alter fidelity suggests new possibilities for targeting the viral RdRp for antiviral drug development.

Adenosine Monophosphate↗
PubMed2001

Evolution of cell recognition by viruses.

Evolution of receptor specificity by viruses has several implications for viral pathogenesis, host range, virus-mediated gene targeting, and viral adaptation after organ transplantation and xenotransplantation, as well as for the emergence of viral diseases. Recent evidence suggests that minimal changes in viral genomes may trigger a shift in receptor usage for virus entry, even into the same cell type. A capacity to exploit alternative entry pathways may reflect the ancient evolutionary origins of viruses and a possible role as agents of horizontal gene transfers among cells.

Animals↗
PubMed2006

Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection.

Virus-specific CD8+ T cells play a central role in the outcome of several viral infections, including hepatitis B virus (HBV) infection. A key feature of virus-specific CD8+ T cells is the development of memory. The mechanisms resulting in the establishment of T-cell memory are still only poorly understood. It has been suggested that T-cell memory may depend on the survival of virus-specific CD8+ T cells in the contraction phase. Indeed, a population of effector cells that express high levels of the interleukin-7 receptor alpha chain (CD127) as the precursors of memory CD8+ T cells has recently been identified in mice. However, very little information is currently available about the kinetics of CD127 expression in an acute resolving viral infection in humans and its association with disease pathogenesis, viral load, and functional and phenotypical T-cell characteristics. To address these important issues, we analyzed the HBV-specific CD8+ T-cell response longitudinally in a cohort of six patients with acute HBV infection who spontaneously cleared the virus. We observed the emergence of CD127 expression on antigen-specific CD8+ memory T cells during the course of infection. Importantly, the up-regulation of CD127 correlated phenotypically with a loss of CD38 and PD-1 expression and acquisition of CCR7 expression: functionally with an enhanced proliferative capacity and clinically with the decline in serum alanine aminotransferase levels and viral clearance. These results suggest that the expression of CD127 is a marker for the development of functionally and phenotypically defined antigen-specific CD8+ memory T cells in cleared human viral infections.

Acute Disease↗
PubMed1977

[Viral encephalitis (etiology, pathogenesis, classification)].

The existing classifications of viral encephalitis are based on mixed, heterogenous principles. The author on the grounds of comparing modern data, related to the etiology, pathogenesis, predilectiveness, gives his suggestions as to a new classification of viral encephalitis. This classification is structured according to the pathogenetical principles, with a consideration of the different variants of the dynamics and polymorphism of separate nozological forms, depending upon the interrelationships of the viral and the immunity factors.

Clinical Trials as Topic↗