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At least 19 recordsLinked to original sources

PubMed2000

[Neuronal expression of foreign genes with recombinant rabies virus variants].

Rabies virus variants obtained by recombinant DNA techniques enabled us to use the high neurotropism of rabies virus to express foreign genes (e.g: Chloramphenicol Acetyl Transferase gene) in neuronal cell cultures as well as in rodent brain. The foreign gene was inserted in the viral pseudogene region; this insertion did not affect the neurotropism of rabies virus, as shown by infection of neuronal cell cultures without any major cytopathic effects for several days. Stereotaxic inoculation of these rabies virus variants into rat striatum indicated that insertion of the foreign gene did not alter the viral axonal transport and the subsequent widespread brain infection. These data allow to consider rabies virus as a vector for the selective expression of foreign genes in neurons.

Animals↗

PubMed2003

A glucocorticoid response element in the LTR U3 region of Friend murine leukaemia virus variant FIS-2 enhances virus production in vitro and is a major determinant for sex differences in susceptibility to FIS-2 infection in vivo.

The nucleotide sequence of the Friend murine leukaemia virus variant FIS-2 LTR has high identity with the closely related Friend murine leukaemia virus (F-MuLV) LTR, except for the deletion of one direct repeat, a few point mutations and the generation of a glucocorticoid response element (GRE) in the U3 region. The GRE can mediate gene induction by glucocorticoids, mineral corticoids, progesterone and androgens, and it has been shown that incorporation of a GRE(s) within the LTR can increase the transcriptional activity of retroviral enhancers. We have previously reported an increased early virus replication in male mice compared with female mice when infected with a virus containing the FIS-2 LTR and have proposed that the GRE might contribute to this sex difference. In the present study, we introduced a single point mutation in the GRE and performed comparative studies in NIH 3T3 cells and in young adult male and female NMRI mice. We found that significantly more virus was produced from NIH 3T3 cells infected with wt FIS-2 than from cells infected with the FIS-2 GRE mutant and that this difference was further augmented by glucocorticoids. The glucocorticoid antagonist RU486 inhibited virus production in a dose-dependent manner. The wt FIS-2 disseminated significantly faster than the FIS-2 GRE mutant in both male and female mice. There was no significant difference in the dissemination rate between male and female mice infected with the FIS-2 GRE mutant. Hence, the GRE in the FIS-2 LTR is one determinant of the significant sex difference in susceptibility to FIS-2 infection.

3T3 Cells↗

PubMed2003

Decreasing sensitivity to RANTES (regulated on activation, normally T cell-expressed and -secreted) neutralization of CC chemokine receptor 5-using, non-syncytium-inducing virus variants in the course of human immunodeficiency virus type 1 infection.

In approximately half of human immunodeficiency virus (HIV) type 1-infected individuals, the development of CXC chemokine receptor 4-using, syncytium-inducing (SI) virus variants precedes a rapid progression to acquired immunodeficiency syndrome (AIDS). In other individuals, only CC chemokine receptor 5-using (R5), non-SI (NSI) virus variants are present throughout infection. These individuals may be either long-term survivors (LTSs) or rapid progressors. The basis for this variable disease progression in individuals with only R5 virus variants is not yet fully understood. In this study, the beta-chemokine sensitivity of biological HIV-1 clones isolated from 13 individuals who harbored only R5, NSI virus variants (7 LTSs and 6 progressors) was investigated. We found a statistically significant decrease in sensitivity of virus variants to RANTES (regulated on activation, normally T cell-expressed and -secreted) neutralization during the course of progressive infection, but not during follow-up of LTSs. Our data suggest that a role exists for RANTES neutralization sensitivity of HIV-1 in AIDS pathogenesis.

Chemokine CCL5↗

PubMed1998

Different distribution of H1-H2 Epstein-Barr virus variant in oropharyngeal virus and in biopsies of Hodgkin's disease and in nasopharyngeal carcinoma from Algeria.

In a previous study of Epstein-Barr virus (EBV) strains in North African nasopharyngeal carcinoma (N PC) biopsies, we have found that the viral strain present was of A/F/W'-I'/Xhol kept/H1-H2 type, while the strain associated with Chinese NPC was the A/"f"/W'I'/Xhol lost/H type. Using the restriction fragment length polymorphism (RFLP) and PCR-RFLP methods, the present study analyzed the H1-H2 variant in different clinical samples from Algeria, including the saliva of healthy EBV-positive individuals and patients with NPC or Hodgkin's disease (HD), as well as HD biopsies and lymphoblastoid cell lines (LCLs) established from the oropharyngeal virus-infected cells. Our results demonstrate that, in contrast to the H1-H2 variant found in NPC biopsies, the H genotype was dominant in HD biopsies. Moreover, H genotype was also dominant in the oropharynx of healthy EBV-positive individuals, of patients with NPC and with HD. Our results clearly indicate that in North Africa the EBV strain present of NPC biopsies is different from that shed in the oropharynx. This may suggest a specific distribution of the H1-H2 variant in the NPC epithelial tumor, whereas the H genotype is dominant in HD biopsies and in the oropharynx. The specific association of both viral strains with these 2 distinct diseases in North Africa may reflect a difference in tumorigenicity.

Algeria↗

PubMed1992

Pathogenicity of feline leukemia virus is commonly associated with variant viruses.

Many of the serious diseases resulting from feline leukemia virus (FeLV) infection are associated with the generation of novel variant viruses. The prototype FeLV-A virus is highly stable and circulates in the cat population without apparent antigenic change. However, recombination with cellular oncogenes produces viruses which cause leukemia or other malignant diseases. Other recombinants within the env genes of FeLV-A and endogenous FeLV are recognized as belonging to a second subgroup, FeLV-B, the presence of which is correlated with an increased risk of infection with FeLV and a higher incidence of leukemia. Mutants of FeLV which affect the env gene are phenotypically of a third subgroup, FeLV-C, and have a close association with erythroid aplasia. None of these viruses, apart from FeLV-B, is transmitted further in nature. Therefore the generation of these novel viruses and the production of disease is an inadvertent consequence of FeLV infection.

Anemia↗

PubMed1989

A neutralization-resistant Theiler's virus variant produces an altered disease pattern in the mouse central nervous system.

Theiler's murine encephalomyelitis virus infection of mice is an animal model for human demyelinating diseases. To further define the role of this virus in the disease process, we selected a virus variant resistant to neutralization by a monoclonal antibody to VP-1. This virus variant was then injected into SJL/J mice. Central nervous system tissue was compared between variant virus- and wild-type virus-infected mice. Within the brain, no large differences were observed between the two groups as to the distribution of inflammatory infiltrates around the injection site and the number of viral antigen-positive cells during the first weeks of the observation period. In contrast, in the spinal cord major differences were found between variant virus- and wild-type virus-infected mice regarding the number of inflammatory lesions, infected cells, and the size of the areas involved with time. By immunohistochemistry, equivalent numbers of infected cells could be found in the spinal cord 1 week postinfection (p.i.): however, after that time, the number of infected cells in the wild-type virus-infected mice continued to increase, whereas the virus-positive cells from the variant virus-infected mice gradually decreased. Thus, the number of viral antigen-containing cells peaked by 1 week p.i. in the variant virus-infected animals. Conversely, the number of infected cells in the spinal cords from mice inoculated with wild-type virus steadily increased until 8 weeks p.i. At this time (8 weeks p.i.), no more variant virus antigen-positive cells could be observed within the spinal cord. Plaque assay of central nervous system tissue confirmed these differences between the two groups observed by immunohistochemistry. No infectious variant virus could be isolated after 2 weeks p.i. from the brain and 4 weeks p.i. from the spinal cord, whereas infectious wild-type virus could be detected up to the end of the observation period (12 weeks p.i.). Virus which was isolated from variant virus-infected mice still retained the neutralization-resistant phenotype. These studies emphasize the important biological in vivo activity of Theiler's virus VP-1 in determining neurovirulence.

Animals↗

PubMed1992

Genetic mechanisms of antigenic variation in infectious bursal disease virus: analysis of a naturally occurring variant virus.

The major immunogenic protein VP2 from a pathogenic field isolate (variant A virus) of infectious bursal disease virus (IBDV) was cloned and sequenced to examine antigenic variations. The VP2 open reading frame consists of 1509 nucleotides and codes for a 503 amino acid protein. Overall, the VP2 amino acid sequence of the variant A virus shares 98.6% identity with VP2 genes from other published IBDV strains. However, within the central region of VP2 (amino acids 222-334) lies a highly divergent area that we have termed the variable domain. Relative to five other IBDV isolates, a total of six amino acid changes occur within the variable domain of the variant A virus. At positions 284-288, a substitution of isoleucine to threonine, a decrease in the number of Chou and Fasman beta turns, and a switch from a hydrophilic to a hydrophobic region are found only in the variant A virus. Together these changes predict a decrease in antigenicity as determined by calculation of potential antigenic sites. This suggests that only minor changes within VP2 contributed to the emergence of a variant virus that can cause disease in immunized birds.

Amino Acid Sequence↗

PubMed1990

Generation of seal influenza virus variants pathogenic for chickens, because of hemagglutinin cleavage site changes.

Influenza virus A/seal/Mass/1/80 (H7N7) was adapted to grow in MDCK cells and chicken embryo cells (CEC) in the absence of exogenous protease. The biological properties of the virus variants obtained coincided with intracellular activation of the hemagglutinin (HA) by posttranslational proteolytic cleavage and depended on the cell type used for adaptation. MDCK cell-adapted variants contained point mutations in regions of the HA more distant from the cleavage site. It is proposed that these mutations are probably responsible, through an unknown mechanism, for enhanced cleavability of HA in MDCK cells. Such virus variants were apathogenic in chickens. CEC-adapted variants, on the other hand, contained an insertion of basic amino acids at the HA cleavage site, in addition to scattered point mutations. The insertions converted the cleavage sites in the variant virus HAs so that they came to resemble the cleavage site found in highly pathogenic avian influenza viruses. CEC variants with such cleavage site modifications were highly pathogenic for chickens. The lethal outcome of the infection in chickens demonstrated for the first time that an influenza virus derived from a mammalian species can be modified during adaptation to a new cell type to such an extent that the resulting virus variant becomes pathogenic for an avian species.

Amino Acid Sequence↗

PubMed1986

Effects of antibodies and interferon on mumps virus persistently infected L929 cells. Generation of variant viruses in the cells during incubation with monoclonal antibodies and interferon.

We studied the effect of antibodies and interferon (IFN) on L929 cells persistently infected with mumps virus (MuV). The persistent infection was maintained by horizontal transmission of the virus within the culture but was regulated by endogenously produced IFN (8). The maintenance of the persistently infected cells in the continuous presence of anti-MuV serum suppressed the production of infectious virus. No virus antigen-positive cells were detected beyond 14 passages. Once antiserum was removed from the seemingly "cured cultures", however, a small number of antigen-positive cells appeared and the release of infectious virus into the culture fluid resumed. Even after 67 passages (200 days) of culture in the presence of anti-serum, the virus reappeared in the culture. At least 0.01 per cent of L929 cells in cultures maintained under antiserum harbored the virus without expression of virus antigen. The virus recovered from such cells was temperature sensitive. The infection of fresh L929 cells with the variant led to noncytocidal persistent infection which was maintained by propagation of virus-infected cells. MuV carrier cultures could be cured by serial cultivation in medium containing the mixture of antiserum and IFN. When L-MuV cells were subcultured with medium containing neutralizing monoclonal antibodies (MoAbs), antibody-resistant variant viruses were rapidly generated and selected. In the presence of IFN variant viruses resistant to IFN were generated. In view of the small amount of virus produced from persistently infected cells, variant viruses appeared to be generated in an unusually high frequency in carrier cultures. Thus, this experimental system may offer a useful in vitro model for studying antigenic variation and generation of various variant viruses.

Animals↗

PubMed1994

Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope.

Mutations that abrogate recognition of a viral epitope by class I-restricted cytotoxic T lymphocyte (CTL) can lead to viral escape if the CTL response against that epitope is crucial for viral clearance. The likelihood of this type of event is low when the CTL response is simultaneously directed against multiple viral epitopes, as has been recently reported for patients with acute self-limited hepatitis B virus (HBV) infection. The CTL response to HBV is usually quite weak, however, during chronic HBV infection, and it is generally acknowledged that this is a major determinant of viral persistence in this disease. If such individuals were to produce a mono- or oligospecific CTL response, however, negative selection of the corresponding mutant viruses might occur. We have recently studied two HLA-A2-positive patients with chronic hepatitis B who, atypically, developed a strong HLA-A2-restricted CTL response against an epitope (FLPSDFFPSV) that contains an HLA-A2-binding motif located between residues 18-27 of the viral nucleocapsid protein, hepatitis B core antigen (HBcAg). These patients failed, however, to respond to any of other HLA-A2-restricted HBV-derived peptides that are generally immunogenic in acutely infected patients who successfully clear the virus. Interestingly, DNA sequence analysis of HBV isolates from these two patients demonstrated alternative residues at position 27 (V --> A and V --> I) and position 21 (S --> N, S --> A, and S --> V) that reduced the HLA and T cell receptor-binding capacities of the variant sequences, respectively. Synthetic peptides containing these alternative sequences were poorly immunogenic compared to the prototype HBc18-27 sequence, and they could not be recognized by CTL clones specific for the prototype peptide. While we do not know if the two patients were originally infected by these variant viruses or if the variants emerged subsequent to infection because of immune selection, the results are most consistent with the latter hypothesis. If this is correct, the data suggest that negative selection of mutant viral genomes might contribute to viral persistence in a subset of patients with chronic HBV infection who express a narrow repertoire of anti-HBV CTL responses.

Acute Disease↗

PubMed1995

Isolation and characterization of a naturally occurring parainfluenza 3 virus variant.

A parainfluenza 3 virus variant which failed to react with parainfluenza 3 virus-specific monoclonal anti-bodies from two commercial sources was isolated from a 14-month-old boy. Analysis of the coding region of the hemagglutinin-neuraminidase gene identified 36 nucleotide changes and 4 amino acid changes compared with a consensus sequence derived from strains isolated from 1957 through 1983. Two unique amino acid changes occurred at positions 174 and 283, which are close to identified epitopes in the hemagglutinin-neuraminidase protein. Ongoing viral surveillance to detect variants is important, particularly in regard to vaccine development.

Antibodies, Monoclonal↗

PubMed1980

Viral hemorrhagic septicemia of rainbow trout: selection of a thermoresistant virus variant and comparison of polypeptide synthesis with the wild-type virus strain.

Serial passage of viral hemorrhagic septicemia virus at gradually increasing temperature selected for a variant virus that replicates at 25 degrees C and has a low pathogenicity for rainbow trout. Viral hemorrhagic septicemia virus-specific polypeptide synthesis was examined in epithelioma papulosum cyprini cells infected with either a wild-type strain or a thermoresistant variant. The wild-type N and M1 proteins were synthesized throughout the course of infection, whereas L, G, and M2 were more actively translated later in the replication cycle. The wild-type strain was more cytotoxic at 25 than at 14 degrees C despite the fact that no translation could be evidenced when the temperature was raised. When epithelioma papulosum cyprini cells were infected with the variant virus, the kinetic study was obstructed since protein synthesis was difficult to observe by the pulse method at a low multiplicity of infection and aborted when the multiplicity of infection was raised. The variant was less cytotoxic at 25 degrees C than wild-type virus.

Animals↗

PubMed1998

Selection of virus variants and emergence of virus escape mutants after immunization with an epitope vaccine.

In this report, we assessed the evolution of the cytotoxic T-lymphocyte (CTL) response induced by an epitope vaccine. In two macaques immunized with a mixture of lipopeptides derived from simian immunodeficiency virus (SIV) Nef and Gag proteins, CTL responses were directed against the same, single epitope of the Nef protein (amino acids 128 to 137) presenting an alanine at position 136 (Nef 128-137/136A). However, after 5 months of SIV infection, peripheral blood mononuclear cells from both macaques lost their ability to be stimulated by autologous SIV-infected cells while still retaining their capacity to generate cytotoxic responses after specific Nef 128-137/136A peptide stimulation. The sequences of the pathogenic viral isolate used for the challenge showed a mixture of several variants. Within the Nef epitopic sequence from amino acids 128 to 137, 82% of viral variants expressed the epitopic peptide Nef 128-137/136A; the remaining variants presented a threonine at position 136 (Nef 128-137/136T). In contrast, sequence analysis of cloned proviral DNA obtained from both macaques 5 months after SIV challenge showed a different pattern of quasi-species variants; 100% of clones presented a threonine at position 136 (Nef 128-137/136T), suggesting the disappearance of viral variants with an alanine at this position under antiviral pressure exerted by Nef 128-137/136A-specific CTLs. In addition, 12 months after SIV challenge, six of eight clones from one macaque presented a glutamic acid at position 131 (Nef 128-137/131E+136T), which was not found in the infecting isolate. Furthermore, CTLs generated very early after SIV challenge were able to lyse cells sensitized with the Nef 128-137/136A epitope. In contrast, lysis was significantly less effective or even did not occur when either the selected peptide Nef 128-137/136T or the escape variant peptide Nef 128-137/131E+136T was used in a target cell sensitization assay. Dose analysis of peptides used to sensitize target cells as well as a major histocompatibility complex (MHC)-peptide stability assay suggested that the selected peptide Nef 128-137/136T has an altered capacity to bind to the MHC. These data suggest that CTL pressure leads to the selection of viral variants and to the emergence of escape mutants and supports the fact that immunization should elicit broad CTL responses.

AIDS Vaccines↗

PubMed1986

Very rapid generation/amplification of defective interfering particles by vesicular stomatitis virus variants isolated from persistent infection.

Multiply cloned variants of vesicular stomatitis virus (VSV) were found to generate/amplify defective interfering (DI) particles at a rate greatly exceeding the rates normally observed for wild-type VSV (or for other mutants of VSV). A single undiluted passage of the first clonal pool of this variant virus produced concentrated visible bands of DI particles on sucrose gradients whereas wild-type and other mutant strains of VSV required from three to six or more serial undiluted passages. Since DI particle amplification by wild-type VSV at each undiluted passage can exceed 10,000-fold enrichment, these variant virus clones were generating/amplifying DI particles many millions of times more rapidly than were wild-type and other mutant strains of VSV. This rate of generation/amplification is so high that it was not feasible to obtain accurate estimates of the rates of generation (or amplification) of these DI particles.

Animals↗

PubMed1991

Restricted virus replication in the spinal cords of nude mice infected with a Theiler's virus variant.

The Daniels strain of Theiler's murine encephalomyelitis produces a chronic disease which is an animal model for human demyelinating disorders. Previously, we selected a neutralization-resistant virus variant producing an altered and diminished central nervous system disease in immunocompetent mice which was evident during the later stage of infection (after 4 weeks) (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). The exact epitope determining neurovirulence was precisely mapped to a capsid protein, VP-1, and represents a neutralizing region (A. Zurbriggen, J. M. Hogle, and R. S. Fujinami, J. Exp. Med. 170:2037-2049, 1989). Here, we present experiments with immunoincompetent animals to determine viral replication, spread, and targeting to the central nervous system in the absence of detectable antibodies or functional T cells. Nude mice were infected orally, and the virus was monitored by plaque assay, immunohistochemistry, and in situ hybridization. Early during the infection (1 week), the variant virus induced an acute disease comparable to that induced by the wild-type virus in these nude mice. Alterations in tropism in the central nervous system were not apparent when wild-type parental Daniels strain virus was compared with the variant virus. Moreover, variant virus replicated in tissue culture (BHK-21 cells) to similarly high titers in a time course identical to that of the wild-type virus (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). However, replication of the variant virus versus the wild-type virus within the spinal cord of athymic nude mice infected per os was substantially restricted by 6 weeks postinfection. Therefore, the reduced neurovirulence in the later stage (6 weeks) of the disease is most likely due to a diminished growth rate or spread of the variant virus in the central nervous system rather than to marked differences in viral tropism.

Animals↗

PubMed1991

Ability of a mutagenized virus variant to protect young lambs from Rift Valley fever.

A live attenuated vaccine virus variant of Rift Valley fever (RVF) virus was developed by passaging a human isolate in tissue culture under the influence of the mutagen 5-fluorouracil. This virus variant (MV P12) has been assessed in this study as to its suitability as a vaccine, by testing its pathogenicity in young lambs and measuring its ability to induce a protective immune response. Even high doses of the vaccine virus failed to induce any of the clinical or histopathologic changes associated with classical RVF virus infection. Although the vaccine induced mild pyrexia when given in high doses, viremia was not induced. Neutralizing antibody and a protective immune response was elicited with even low doses of vaccine virus. These data, along with data of other workers on the lack of abortigenicity of this virus variant, indicate that the MV P12 variant of RVF virus is an excellent candidate for a safe and effective vaccine against RVF.

Animals↗

PubMed1998

In vivo evolution of a novel, syncytium-inducing and cytopathic feline leukemia virus variant.

Studies of feline leukemia virus (FeLV) have illustrated the importance of the genotype of the infecting virus in determining disease outcome. In FeLV infections, as in other retroviral infections, it is less clear how virus variants that evolve from the transmitted virus affect pathogenesis. We previously reported an analysis of the genotypic changes that occur in the viral envelope gene (env) in cats infected with a prototype transmissible FeLV clone, 61E (J. Rohn, M. Linenberger, E. Hoover, and J. Overbaugh, J. Virol. 68:2458-2467, 1994). In one cat, each variant (81T) had evolved, in addition to scattered amino acid changes, a four-amino-acid insertion with respect to 61E. This insertion was located at the same site in the extracellular envelope glycoprotein where the immunodeficiency-inducing molecular clone 61C possesses a six-amino-acid insertion critical for its pathogenic phenotype, although the sequences of the insertions were distinct. To determine whether acquisition of the four-amino-acid insertion was associated with a change in the replication or cytopathic properties of the virus, we constructed chimeras encoding 81T env genes in a 61E background. One representative chimeric virus, EET(TE)-109, was highly cytopathic despite the fact that it replicated with delayed kinetics in the feline T-cell line 3201 compared to the parental 61E virus. The phenotype of this virus was also novel compared to other FeLVs, including both the parental virus 61E and the immunodeficiency-inducing variant 61C, because infection of T cells was associated with syncytium formation. Moreover, in single-cycle infection assays, the 81T-109 envelope demonstrated receptor usage properties distinct from those of both 61E and 61C envelope. Thus, these studies demonstrate the evolution of a novel T-cell cytopathic and syncytium-inducing FeLV in the host. The 81T virus will be valuable for dissecting the mechanism of T-cell killing by cytopathic variants in the FeLV model.

Amino Acid Sequence↗

PubMed2001

Epidemiologic characteristics of rabies virus variants in dogs and cats in the United States, 1999.

OBJECTIVE: To evaluate epidemiologic features of rabies virus variants in dogs and cats in the United States during 1999 and assess the role of bat-associated variants. DESIGN: Epidemiologic survey. SAMPLE POPULATION: Rabies viruses from 78 dogs and 230 cats. PROCEDURE: Brain specimens from rabid dogs and cats were submitted for typing of rabies virus. Historical information, including ownership and vaccination status, was obtained for each animal. Specimens were typed by use of indirect fluorescent antibody assay or reverse transcriptase polymerase chain reaction assay and nucleotide sequence analysis. RESULTS: Nearly all animals were infected with the predicted terrestrial rabies virus variant associated with the geographic location of the submission. A bat-associated variant of rabies virus was found in a single cat from Maryland. More than half (53%) of submitted animals were classified as owned animals, and most had no known history of vaccination. One vaccination failure was reported in a dog that did not receive a booster dose of rabies vaccine after exposure to a possibly rabid animal. CONCLUSIONS AND CLINICAL RELEVANCE: Bat-associated rabies virus variants were not a common cause of rabies in dogs and cats during 1999. Vaccine failures were uncommon during the study period. Because most rabid dogs and cats were unvaccinated and were owned animals rather than strays, educational campaigns targeting owners may be useful.

Animals↗