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PubMed1987

Further characterization of the interaction of polyoma virus and simian virus 40 with embryonal carcinoma cells.

The host restriction imposed on polyoma virus by embryonal carcinoma cells can be circumvented by mutations in the enhancer region of the viral genome. In addition, expression of the early viral genes can be induced by differentiating cells transfected with purified viral DNA. Although no host-range mutants of SV40 have been isolated, expression of T antigen from episomal genomes can be induced by differentiating the embryonal carcinoma cells transfected with microgram quantities of DNA. Further, transient expression of T antigen can be observed in the embryonal carcinoma cells following transfection with large amounts of viral DNA. In addition, replication of the A2 strain of polyoma in F9 cells is enhancer dependent but the SV40 enhancer can functionally substitute for the polyoma enhancer. The F9 host-range mutant TT340 contains five tandem repeats of the region surrounding the origin of replication, and it requires T antigen for replication. The parental strain (Toronto) of the mutant is able to replicate at low levels in a T antigen-dependent manner in F9 cells. This strain also has an unselected host range for PCC4 cells and the mutation in TT340 required for growth on F9 cells does not alter this inherent host range.

Antigens, Viral, Tumor↗
PubMed1994

Identification of a high-molecular-weight cellular protein complex containing the adenovirus DNA binding protein.

The adenovirus DNA binding protein (DBP) functions in a number of diverse processes that include viral DNA replication and host range determination. A subpopulation of DBP has been found to exist in a high-molecular-weight (HMWDBP) complex of greater than 650 kDa. This complex was stable to high salt and low levels of detergent in the presence of DTT at 4 degrees. While the complex prepared in high salt was devoid of nucleic acid, it retained its ability to bind to ssDNA. Electron microscopic (EM) analysis in the presence of M13 ssDNA verified its interaction with ssDNA. The complex exists as particles approximately 25-30 nm based on EM analysis of negatively stained samples in the absence of DNA. No viral replication components were detected in the HMWDBP complex, suggesting that it is not a viral replication complex. The HMWDBP complex prepared under a variety of infection conditions contained a consistent set of proteins. HMWDBP complex was also detected in the absence of viral infection in gmDBP6 cells (a HeLa cell derivative that expresses DBP from the dexamethasone-inducible MMTV promoter). These results suggest that the components of the complex, other than DBP, are host encoded.

Adenoviruses, Human↗
PubMed2003

Host and geographic range extensions of the North American strain of viral hemorrhagic septicemia virus.

Viral hemorrhagic septicemia virus (VHSV) was isolated from populations of Pacific sardine Sardinops sagax from the coastal waters of Vancouver Island, British Columbia, Canada, and central and southern California, USA. The virus was also isolated from Pacific mackerel Scomber japonicus in southern California, from eulachon or smelt Thaleichthys pacificus, and surf smelt Hypomesus pretiosus pretiosus from Oregon, USA. Mortality and skin lesions typical of viral hemorrhagic septicemia in other marine fish species were observed among sardine in Canada and in a few surf smelt from Oregon, but the remaining isolates of VHSV were obtained from healthy appearing fish. The prevalence of VHSV among groups of apparently healthy sardine, mackerel and smelt ranged from 4 to 8%, in California and Oregon. A greater prevalence of infection (58%) occurred in groups of sardine sampled in Canada that sustained a naturally occurring epidemic during 1998-99. A captive group of surf smelt in Oregon exhibited an 81% prevalence of infection with clinical signs in only a few fish. The new isolates were confirmed as North American VHSV and were closely related based on comparisons of the partial nucleotide sequence of the glycoprotein (G) gene. The VHSV isolates from sardine in Canada and California were the most closely related, differing from isolates obtained from other marine fish species and salmonids in British Columbia, Canada, Alaska and Washington, USA. These new virus isolations extend both the known hosts (sardine, mackerel and 2 species of smelt) and geographic range (Oregon and California, USA) of VHSV.

Animals↗
PubMed2005

Suppressors of a host range mutation in the rabbitpox virus serpin SPI-1 map to proteins essential for viral DNA replication.

The orthopoxvirus serpin SPI-1 is an intracellular serine protease inhibitor that is active against cathepsin G in vitro. Rabbitpox virus (RPV) mutants with deletions of the SPI-1 gene grow on monkey kidney cells (CV-1) but do not plaque on normally permissive human lung carcinoma cells (A549). This reduced-host-range (hr) phenotype suggests that SPI-1 may interact with cellular and/or other viral proteins. We devised a genetic screen for suppressors of SPI-1 hr mutations by first introducing a mutation into SPI-1 (T309R) at residue P14 of the serpin reactive center loop. The SPI-1 T309R serpin is inactive as a protease inhibitor in vitro. Introduction of the mutation into RPV leads to the same restricted hr phenotype as deletion of the SPI-1 gene. Second-site suppressors were selected by restoration of growth of the RPV SPI-1 T309R hr mutant on A549 cells. Both intragenic and extragenic suppressors of the T309R mutation were identified. One novel intragenic suppressor mutation, T309C, restored protease inhibition by SPI-1 in vitro. Extragenic suppressor mutations were mapped by a new procedure utilizing overlapping PCR products encompassing the entire genome in conjunction with marker rescue. One suppressor mutation, which also rendered the virus temperature sensitive for growth, mapped to the DNA polymerase gene (E9L). Several other suppressors mapped to gene D5R, an NTPase required for DNA replication. These results unexpectedly suggest that the host range function of SPI-1 may be associated with viral DNA replication by an as yet unknown mechanism.

Amino Acid Sequence↗
PubMed1987

The avian influenza virus nucleoprotein gene and a specific constellation of avian and human virus polymerase genes each specify attenuation of avian-human influenza A/Pintail/79 reassortant viruses for monkeys.

Reassortant viruses which possessed the hemagglutinin and neuraminidase genes of wild-type human influenza A viruses and the remaining six RNA segments (internal genes) of the avian A/Pintail/Alberta/119/79 (H4N6) virus were previously found to be attenuated in humans. To study the genetic basis of this attenuation, we isolated influenza A/Pintail/79 X A/Washington/897/80 reassortant viruses which contained human influenza virus H3N2 surface glycoprotein genes and various combinations of avian or human influenza virus internal genes. Twenty-four reassortant viruses were isolated and first evaluated for infectivity in avian (primary chick kidney [PCK]) and mammalian (Madin-Darby canine kidney [MDCK]) tissue culture lines. Reassortant viruses with two specific constellations of viral polymerase genes exhibited a significant host range restriction of replication in mammalian (MDCK) tissue culture compared with that in avian (PCK) tissue culture. The viral polymerase genotype PB2-avian (A) virus, PB1-A virus, and PA-human (H) virus was associated with a 900-fold restriction, while the viral polymerase genotype PB2-H, PB1-A, and PA-H was associated with an 80,000-fold restriction of replication in MDCK compared with that in PCK. Fifteen reassortant viruses were subsequently evaluated for their level of replication in the respiratory tract of squirrel monkeys, and two genetic determinants of attenuation were identified. First, reassortant viruses which possessed the avian influenza virus nucleoprotein gene were as restricted in replication as a virus which possessed all six internal genes of the avian influenza A virus parent, indicating that the nucleoprotein gene is the major determinant of attenuation of avian-human A/Pintail/79 reassortant viruses for monkeys. Second, reassortant viruses which possessed the viral polymerase gene constellation of PB2-H, PB1-A, and PA-H, which was associated with the greater degree of host range restriction in vitro, were highly restricted in replication in monkeys. Since the avian-human influenza reassortant viruses which expressed either mode of attenuation in monkeys replicated to high titer in eggs and in PCK tissue culture, their failure to replicate efficiently in the respiratory epithelium of primates must be due to the failure of viral factors to interact with primate host cell factors. The implications of these findings for the development of live-virus vaccines and for the evolution of influenza A viruses in nature are discussed.

Animals↗
PubMed2006

Expression of the crucifer-infecting TMV-Cg movement protein in tobacco plants complements in trans a TMV-U1 trafficking-deficient mutant.

Tobamovirus movement proteins play a determinant role in the establishment of infections in plants, allowing the local movement of viral RNA genome through plasmodesmatas. We expressed the movement protein (MP) of the crucifer- and garlic-infecting Tobacco Mosaic Virus strain Cg (TMV-Cg) in both resistant Xanthi NN and sensitive Xanthi nn Nicotiana tabacum plants. MP-Cg function was assayed by inoculating transgenic plants with a trafficking-deficient mutant of TMV strain U1. Following infection, local necrotic lesions were developed in resistant transgenic plants, and a systemic infection was produced in sensitive tobaccos. Thus, movement function of the mutant virus was complemented in trans by MP-Cg expressed in transgenic plants, causing the same symptoms as wild-type strain. We demonstrated that the function of MP-U1 could be replaced efficiently by MP-Cg, even though these proteins share only 36% of identity. Similar hydrophobic patterns of MP-Cg and MP-U1 suggests structure and function conservations of both proteins. This work is an example of how two tobamoviruses differing in their host range help to understand viral movement mechanism during the infection.

Gene Expression↗
PubMed1985

Host cell range of adult T-cell leukemia virus. I. Viral infectivity and binding to various cells as detected by flow cytometry.

Adult T-cell leukemia virus is the member of a human type-C retrovirus family (HTLV) found to be associated with adult T-cell leukemia (ATL) in Japan. In our study, HTLV was isolated from the MT-2 cell line, purified on sucrose gradient and labelled with fluorescein-isothiocyanate (FITC-HTLV). The protein pattern of the virus was determined by SDS-gel electrophoresis and assured by Western blotting using ATL patient serum. Fresh human lymphocytes, separated B and T cells, mouse and rabbit lymphocytes, mouse fibroblasts, and 13 different tumor cell lines were tested in parallel for binding of FITC-HTLV and infectability by the virus. Virus binding to cell receptors was assayed by flow cytometry. Successful infection was monitored by following the expression of HTLV-determined antigen (HTLA). Most of the cells bound FITC-HTLV at levels ranging from 5% to 130% of the MT-2 cell binding. Only fresh human T, mouse and rabbit lymphocytes were infectable by cell-free virus preparations. The results demonstrate that HTLV receptors are present on different types of cells of both human and animal origin, and that infection by the virus is restricted to fewer host cells but not limited to a specific class of human lymphocytes.

Animals↗
PubMed1994

Correlation between high level gp160 expression and reduced CD4 biosynthesis in clonal derivatives of human immunodeficiency virus type 1-infected U-937 cells.

We have compared cytoplasmic CD4 mRNA accumulation, CD4 biosynthesis and steady-state levels of both CD4 protein and mRNA in a variety of clonal derivatives of U-937 cells, chronically infected with human immunodeficiency virus type 1 IIIB (HIV-1), that express various cellular and viral phenotypes. These phenotypes included defective processing of either gp160 or Gag-Pol, viruses with severely limited host-range, and inability to generate viral products. All clones, with the exception of the one that failed to generate viral mRNA and proteins, did not express cell surface CD4. Furthermore, each of these clones had steady-state levels of CD4 mRNA which were either equivalent to or higher than those of the parental U-937 cell line. Patterns of cytoplasmic CD4 mRNA levels resembled those of total RNA, suggesting that CD4 mRNA transport from the nucleus to the cytoplasm was unaffected by HIV-1 infection. Profiles of steady-state levels of the CD4 protein resembled those of CD4 mRNA in the UHC clones, but CD4 biosynthesis was reduced in all clones with the exception of that which failed to express viral products. This report is the first demonstration that steady-state CD4 biosynthesis is reduced in HIV-1-infected cells. In general, there was a good correlation between high levels of expression of gp160 and reduced CD4 biosynthesis. These results suggest that HIV-1 env gene products may contribute to the observed reduction in levels of CD4 biosynthesis.

Blotting, Northern↗
PubMed2001

Receptor-specific targeting mediated by the coexpression of a targeted murine leukemia virus envelope protein and a binding-defective influenza hemagglutinin protein.

The entry of retroviral vectors into cells requires two events: binding to a cell surface receptor and the subsequent fusion of viral and cellular membranes. The host range of a vector is therefore determined largely by the receptor specificity of the fusion protein contained in the outer viral envelope. Previous attempts to generate targeted retroviral vectors have included the addition of targeting ligands to the murine leukemia virus envelope protein (MuLV Env). Although such proteins frequently display modified cell-binding characteristics, the interaction with the targeted receptors fails to trigger virus-cell fusion. Here, we report the use of a binding-defective but fusion-competent hemagglutinin (HA) protein to complement the fusion defect in a chimeric MuLV Env targeted to the Flt-3 receptor. Retroviral vectors containing both proteins showed enhanced transduction of cells expressing Flt-3, which was abrogated by preincubating the target cells with soluble Flt-3 ligand. Furthermore, the fusion function of HA was absolutely required. These data demonstrate that it is possible to separate the binding and fusion events of retroviral entry, using two separate proteins, and suggest that varying the binding protein component in this scheme may allow a general strategy for targeting retroviral vectors.

3T3 Cells↗
PubMed1988

Molecular and biochemical studies of the evolution, infection and transmission of insect bunyaviruses.

Members of the Bunyaviridae family of RNA viruses (bunyaviruses, hantaviruses, nairoviruses, phleboviruses and uukuviruses) have been studied at the molecular and genetic level to understand the basis of their evolution and infection in vertebrate and invertebrate (arthropod) hosts. With the exception of the hantaviruses, these viruses infect and are transmitted by a variety of blood-sucking arthropods (mosquitoes, phlebotomines, gnats, ticks, etc.). The viruses are responsible for infection of various vertebrate species, occasionally causing human disease, morbidity and mortality (e.g. Rift Valley fever, Crimean-Congo haemorrhagic fever, Korean haemorrhagic fever). Genetic and molecular analyses of bunyaviruses have established the coding assignments of the three viral RNA species and documented which viral gene products determine host range and virulence. Ecological studies, with molecular techniques, have provided evidence for bunyavirus evolution in nature through genetic drift (involving the accumulation of point mutations) and shift (RNA-segment reassortment).

Animals↗
PubMed1994

Identification of the threonine phosphorylation sites on the polyomavirus major capsid protein VP1: relationship to the activity of middle T antigen.

Phosphorylation of the polyomavirus major capsid protein VP1 was examined after in vivo 32P labeling of virus-infected cells. Two phosphorylated peptide fragments of VP1 were identified by protease digestion, high-performance liquid chromatography purification, mass spectrometry, and N-terminal sequencing. The peptides from residues 58 to 78 and residues 153 to 173 were phosphorylated on threonine. Site-directed mutations were introduced at these threonine sites, and mutant viruses were reconstructed. A threonine-to-glycine change at residue 63 (mutant G63) and a threonine-to-alanine change at residue 156 (mutant A156) resulted in viruses defective in phosphorylation of the respective peptides after in vivo labeling. Growth of the mutant G63 virus was similar to that of the wild-type virus, but the mutant A156 was inefficient in assembly of 240S viral particles. Polyomavirus nontransforming host range (hr-t) mutants are defective in VP1 threonine phosphorylation when grown in nonpermissive cells (R. L. Garcea, K. Ballmer-Hofer, and T. L. Benjamin, J. Virol. 54:311-316, 1985). Proteolytic mapping of VP1 peptides after in vivo labeling from hr-t mutant virus infections demonstrated that both residues T-63 and T-156 were affected. These results suggest that the block in virion assembly in hr-t mutant viruses is associated with a defect in phosphorylation of threonine 156.

Amino Acid Sequence↗
PubMed2003

Characterization of recombinant nonecotropic murine leukemia viruses from the wild mouse species Mus spretus.

The wild mouse species most closely related to the common laboratory strains contain proviral env genes of the xenotropic/polytropic subgroup of mouse leukemia viruses (MLVs). To determine if the polytropic proviruses of Mus spretus contain functional genes, we inoculated neonates with Moloney MLV (MoMLV) or amphotropic MLV (A-MLV) and screened for viral recombinants with altered host ranges. Thymus and spleen cells from MoMLV-inoculated mice were plated on Mus dunni cells and mink cells, since these cells do not support the replication of MoMLV, and cells from A-MLV-inoculated mice were plated on ferret cells. All MoMLV-inoculated mice produced ecotropic viruses that resembled their MoMLV progenitor, although some isolates, unlike MoMLV, grew to high titers in M. dunni cells. All of the MoMLV-inoculated mice also produced nonecotropic virus that was infectious for mink cells. Sequencing of three MoMLV- and two A-MLV-derived nonecotropic recombinants confirmed that these viruses contained substantial substitutions that included the regions of env encoding the surface (SU) protein and the 5' end of the transmembrane (TM) protein. The 5' recombination breakpoint for one of the A-MLV recombinants was identified in RNase H. The M. spretus-derived env substitutions were nearly identical to the corresponding regions in prototypical laboratory mouse polytropic proviruses, but the wild mouse infectious viruses had a more restricted host range. The M. spretus proviruses contributing to these recombinants were also sequenced. The seven sequenced proviruses were 99% identical to one another and to the recombinants; only two of the seven had obvious fatal defects. We conclude that the M. spretus proviruses are likely to be recent germ line acquisitions and that they contain functional genes that can contribute to the production of replication-competent virus.

Amino Acid Sequence↗
PubMed2004

Rinderpest virus phosphoprotein gene is a major determinant of species-specific pathogenicity.

We previously demonstrated that the rinderpest virus (RPV) hemagglutinin (H) protein plays an important role in determining host range but that other viral proteins are clearly required for full RPV pathogenicity to be manifest in different species. To examine the effects of the RPV nucleocapsid (N) protein and phosphoprotein (P) genes on RPV cross-species pathogenicity, we constructed two new recombinant viruses in which the H and P or the H, N, and P genes of the cattle-derived RPV RBOK vaccine were replaced with those from the rabbit-adapted RPV-Lv strain, which is highly pathogenic in rabbits. The viruses rescued were designated recombinant RPV-lapPH (rRPV-lapPH) and rRPV-lapNPH, respectively. Rabbits inoculated with RPV-Lv become feverish and show leukopenia and a decrease in body weight gain, while clinical signs of infection are never observed in rabbits inoculated with RPV-RBOK or with rRPV-lapH. However, rabbits inoculated with either rRPV-lapPH or rRPV-lapNPH became pyrexic and showed leukopenia. Further, histopathological lesions and high virus titers were clearly observed in the lymphoid tissues from animals infected with rRPV-lapPH or rRPV-lapNPH, although they were not observed in rabbits infected with RPV-RBOK or rRPV-lapH. The clinical, virological, and histopathological signs in rabbits infected with the two new recombinant viruses did not differ significantly; therefore, the RPV P gene was considered to be a key determinant of cross-species pathogenicity.

Animals↗
PubMed2006

Pegylated interferon plus ribavirin for chronic hepatitis C: the role of combination therapy today, tomorrow and in the future.

Approximately 123 million people worldwide are infected with hepatitis C virus (HCV). The majority of those infected with the virus develop chronic progressive liver disease that over time can result in cirrhosis, end-stage liver disease, hepatocellular carcinoma and death. The goal of treatment is viral eradication. The recognised standard of care for chronic hepatitis C is the combination of pegylated interferon plus ribavirin, which has been shown to be effective in treatment-naïve patients, including those with persistently normal ALT levels, and in patients with HIV-HCV coinfection. Two pegylated interferons are commercially available, both of which have distinct pharmacokinetic properties that necessitate different dosing strategies. With the standard of care, overall virological response rates have exceeded 50% in randomised, multinational phase III studies. Viral response rates are heterogenous and are influenced by a range of viral and host-specific factors. By far, the most important factors influencing treatment outcomes are HCV genotype and baseline HCV RNA level. Customisation of therapy based on baseline factors is recommended in treatment guidelines in order to maximise cure rates. Pegylated interferon plus ribavirin has been shown to be effective and safe in patients with HIV-HCV coinfection and is now recommended in this important and growing subpopulation. Ongoing efforts to improve treatment outcomes are focused on dynamic customisation of therapy based on the on-treatment response to therapy. Treatment of nonresponders to previous interferon-based therapies is an important area under investigation. Although several promising oral agents have been identified and are currently in clinical development, it seems likely that pegylated interferon will remain the backbone of therapy for years to come.

Antiviral Agents↗
PubMed2000

Vaccination with DNA encoding internal proteins of influenza virus does not require CD8(+) cytotoxic T lymphocytes: either CD4(+) or CD8(+) T cells can promote survival and recovery after challenge.

DNA vaccination offers the advantages of viral gene expression within host cells without the risks of infectious virus. Like viral vaccines, DNA vaccines encoding internal influenza virus proteins can induce immunity to conserved epitopes and so may defend the host against a broad range of viral variants. CD8(+) cytotoxic T lymphocytes (CTL) have been described as essential effectors in protection by influenza nucleoprotein (NP), although a lesser role of CD4(+) cells has been reported. We immunized mice with plasmids encoding influenza virus NP and matrix (M). NP + M DNA allowed B6 mice to survive otherwise lethal challenge infection, but did not protect B6-beta(2)m(-/-) mice defective in CD8(+) CTL. However, this does not prove CTL are required, because beta(2)m(-/-) mice have multiple immune abnormalities. We used acute T cell depletion in vivo to identify effectors critical for defense against challenge infection. Since lung lymphocytes are relevant to virus clearance, surface phenotypes and cytolytic activity of lung lymphocytes were analyzed in depleted animals, along with lethal challenge studies. Depletion of either CD4(+) or CD8(+) T cells in NP + M DNA-immunized BALB/c mice during the challenge period did not significantly decrease survival, while simultaneous depletion of CD4(+) and CD8(+) cells or depletion of all CD90(+) cells completely abrogated survival. We conclude that T cell immunity induced by NP + M DNA vaccination is responsible for immune defense, but CD8(+) T cells are not essential in the active response to this vaccination. Either CD4(+) or CD8(+) T cells can promote survival and recovery in the absence of the other subset.

Amino Acid Sequence↗
PubMed1988

Pathogenic and host range determinants of the feline aplastic anemia retrovirus.

Feline leukemia virus (FeLV) C-Sarma (or FSC) is a prototype of subgroup C FeLVs, which induce fatal aplastic anemia in outbred specific-pathogen-free (SPF) cats. FeLV C isolates also possess an extended host range in vitro, including an ability, unique among FeLVs, to replicate in guinea pig cells. To identify the viral determinants responsible for the pathogenicity and host range of FSC we constructed a series of proviral DNAs by exchanging gene fragments between FSC and FeLV-61E (or F6A), the latter of which is minimally pathogenic and whose host range in vitro is restricted to feline cells. Transfer of an 886-base-pair (bp) fragment of FSC, encompassing the codons for 73 amino acids at the 3' end of pol (the integrase/endonuclease gene) and the codons for 241 amino acids of the N-terminal portion of env [the extracellular glycoprotein (gp70) gene], into the F6A genome was sufficient to confer onto chimeric viruses the ability to induce fatal aplastic anemia in SPF cats. In contrast, no chimera lacking this sequence induced disease. When assayed in vitro, all chimeric viruses containing the 886-bp fragment of FSC acquired the ability to replicate in heterologous cells, including dog and guinea pig cells. Thus, the pathogenic and the host range determinants of the feline aplastic anemia retrovirus colocalize to a 3' pol-5' env region of the FSC genome and likely reside within a region encoding 241 amino acid residues of the N terminus of the extracellular glycoprotein.

Anemia, Aplastic↗