Low interferon binding activity of two human cell lines which respond poorly to the antiviral and antiproliferative activity of interferon.
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2',5'-Oligoadenylate Synthetase↗
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Sequence of the 5' end of the Sendai virus genome and its variable representation in complementary form at the 3' ends of copy-back defective interfering RNA species: identification of the L gene terminus.
Direct sequencing showed that the 5' termini of several defective interfering RNA species, both fusion and copy-back types, were homologous to the 5' terminus of the Sendai virus genome. Size analyses of spontaneously formed terminal duplexes (stems) of three copy-back defective interfering RNA species revealed variable extents of terminal complementarity, ranging from about 155 to 210 nucleotides. Direct sequencing of the 3' terminus of one of these copy-back RNA species demonstrated its complementarity to the 5'-terminal sequence of the virus genome. This copy-back sequence contained, in complementary form, the 5' terminus of the L gene, comprising the same sequence, 3'-AUUCUUUUU-5', that was previously identified at the 5' ends of the five other major Sendai virus genes.
Base Sequence↗
Inhibition of SV40 DNA synthesis by vesicular stomatitis virus in doubly infected monkey kidney cells.
Vesicular stomatitis virus (VSV) inhibited SV40 DNA synthesis in doubly infected synchronized Vero cells. Gel-electrophoretic profiles demonstrated that SV40 DNA monomers accumulated in all stages of supercoiling, regardless of whether cells were superinfected with VSV early or late in the S phase. These gel profiles were indistinguishable from ones obtained from SV40-infected, cycloheximide-treated cells in the absence of VSV infection. Radiolabel in the partial supercoils could be chased into supercoils, but only by restoring protein synthesis. The relative rates of SV40 DNA chain elongation were determined in VSV-superinfected and nonsuperinfected cells. The gradients of 3H incorporation as a function of distance from the origin of replication in pulse-labeled form I DNA were unaffected by VSV. It is concluded that VSV inhibition of SV40 DNA synthesis is an indirect result of inhibition of host cell protein synthesis and it is suggested that incompletely supercoiled SV40 chromatin is not a good template for DNA synthesis.
Animals↗
Defective interfering influenza RNAs of polymerase 3 gene contain single as well as multiple internal deletions.
Defective interfering (DI) RNAs of influenza virus arise from polymerase genes by internal deletions. Utilizing the recombinant DNA cloning and sequencing techniques we have determined the nucleotide sequence of two DI RNAs of L clone of A/WSN/33 (L2a-7 and L2a-17) which are of polymerase 3 origin. L2a-7 DI RNA is 659 nucleotides long and contains a single internal deletion of 1682 nucleotides (nucleotide position 273 to 1954) of P3 gene. L2a-17 DI RNA (611 nucleotides long), on the other hand, contains two internal deletions: one of 1682 nucleotides at the identical position as that in L2a-7, the other 48 nucleotides at the nucleotide position 2032 to 2079 of P3 gene. Except for a few base mismatches the sequence of DI RNAs are identical to the corresponding portion of the P3 gene including the 5' and the 3' termini. Since these two DI RNAs contain one identical deletion but differ in the other deletion as well as in base mismatches, these two DI RNAs appear to originate from a progenitor DI RNA rather than independently from the progenitor P3 gene. The sequences around the deletion point do not reflect a consensus sequence for the origin of these deletions and suggest the role of multiple mechanisms in the generation and evolution of influenza DI RNAs.
Base Sequence↗
Factors that affect genetic interaction during mixed infection with temperature-sensitive mutants of simian rotavirus SA11.
A number of factors that affect genetic interaction during mixed infection with temperature-sensitive mutants of simian rotavirus SA11 have been examined. (1) Statistical analyses of recombination frequency (RF) indicated that (a) the variability noted in RF was not related to variations in experimental conditions and (b) a linear map of the mutations could not be drawn. (2) The wild phenotype of recombinant progeny was stable on passage. (3) Aggregates of progeny virus or heterozygous progeny virus particles did not contribute significantly to the observed RF. (4) RF increased in parallel with multiplicity of infection. (5) A maximal, or near maximal, RF was obtained at the earliest time significant recombinants could be detected. (6) Recombination was efficient at nonpermissive temperature. (7) Complementation did not occur or was inefficient. (8) Mutants from all recombination groups interfered with the growth of wild-type virus at both permissive and nonpermissive temperatures.
Genetic Complementation Test↗
Avian leukosis virus-induced osteopetrosis is associated with the persistent synthesis of viral DNA.
DNAs from 19 cases of avian leukosis virus-induced osteopetrosis have been analyzed for viral sequences. Among these were instances of rapid, intermediate, and slow onset osteopetrosis. The DNAs from osteopetrotic bone contained no evidence for osteopetrosis being caused by proviral insertions into or viral transductions of a host protooncogene. Instead, DNAs from osteopetrotic bone displayed evidence for osteopetrosis being associated with the persistent synthesis of viral DNA. Each of the 19 DNAs contained unintegrated as well as integrated viral DNA. Rapid onset osteopetrosis contained about 3X more viral and proviral DNA than intermediate or late onset osteopetrosis. Unintegrated viral DNA could not be detected in DNAs extracted from the bursa bone marrow of osteopetrotic chickens or in DNA extracted from the normal bones of an avian leukosis virus-infected chicken. Thus, the persistent synthesis of unintegrated viral DNA was observed in osteopetrotic but not normal tissues of avian leukosis virus-infected chickens.
Animals↗
Cloning and fine mapping the DNA of equine herpesvirus type one defective interfering particles.
Equine herpesvirus type one (EHV-1) defective interfering (DI) particle DNA fragments were inserted into the XbaI site of the plasmid vector pACYC184. Five DI XbaI fragments, which ranged in molecular weight from 4.5 to 6.7 MDa, were selected for detailed analysis. Each DI DNA clone was labeled with 32P-deoxynucleotides by nick translation and hybridized to genomic digests of EHV-1 standard (STD) DNA bound to nitrocellulose. All five clones were shown to hybridize to DNA sequences derived from the left terminus (0.0-0.04 map units) of the long (L) region and from the short (S) region inverted repeats (IRs, 0.79-0.86 and 0.93-1.00 map units) of the STD EHV-1 genome. Restriction enzyme mapping studies and Southern blot hybridizations employing cloned STD virus DNA fragments as probes revealed that these EHV-1 DI clones contain two major domains: (1) an L terminal region which maps to 0.01-0.04 map units and is highly conserved among all five clones, and (2) a region homologous to the IRs which appears to vary between individual clones.
Cell Transformation, Neoplastic↗
Defective interfering particles of VSVNJ (Ogden), generated by heat treatment, contain multiple internal genomic deletions.
Defective interfering (DI) particles have been isolated from a heat-resistant strain of the New Jersey (Ogden) serotype of vesicular stomatitis virus (VSV). Most of these DI particles contain various portions of all five cistrons of VSV. The two largest DI particles, NJ-121 and NJ-PG2, represent approximately 60% of the standard virus genome and contain both the positive and negative strand leader RNA templates. These two DI particles are transcriptionally active and synthesize both the positive and negative strand leader RNAs in vitro. Virion RNA probe-mRNA hybridizations and cDNA probe-virion RNA hybridizations have shown that NJ-121 contains mainly sequences from the L and G genes. In contrast, NJ-PG2 has portions of the sequences from all five genes of VSV. Smaller DI particles, NJ-121a, NJ-121b, NJ-PG1, and NJ-JM2 representing approximately 50, 38, 28, and 25% of the standard virus genome respectively, were also generated. These DI particles did not have sequences complementary to the positive strand leader RNA template. The mRNA hybridization patterns and results of the genomic RNAs hybridizing to cDNAs of N, NS, M, and G genes of these DI particles showed that they contain parts of information from all five cistrons. Most of the DI particles appear to be generated by multiple deletions throughout the standard virus genome. None of these DI particles interfered heterotypically with VSVIND-HR in BHK21, R(B77), or L2 cells. However, they interfered well with infection by VSVNJ (Hazelhurst).
Chromosome Deletion↗
Equine herpesvirus type 1 defective-interfering (DI) particle DNA structure: the central region of the inverted repeat is deleted from DI DNA.
The inverted repeat (IRs) component of the genome of equine herpesvirus type 1 (EHV-1) is an important region of structure and function. It is a major constituent of the DNA of EHV-1 defective-interfering (DI) particles which have been shown to mediate the coestablishment of oncogenic transformation and persistent infection of hamster embryo cells. In addition, the IRs encodes the single EHV-1 immediate early gene and the 31.5K very early protein. DNA sequences encompassing EHV-1 internal IRs and the joint between the long (L) and short (S) regions were subcloned into the plasmid vectors pBR322 and pUC12. A total of 22 subclones were derived, including six Sa/l subclones in pBR322 and 12 SmaI subclones in pUC12. Individual subclones were employed in Southern blot hybridizations to define subclone homology to repeated, unique, or heterogeneous (het) DNA sequences within the EHV-1 genome. These studies revealed that the EHV-1 het region is contained entirely within the unique long region of the viral genome and is separated from the L/S junction by approximately 1.8 MDa of completely unique DNA sequences. Furthermore, these IRs subclones were employed in blot hybridizations to analyze the integrity of IRs DNA sequences within the cloned DNA of EHV-1 DI particles. These analyses demonstrated that IRs DNA sequences present in DI DNA were extensively rearranged and contained major deletions (0.80-0.83 map units) which removed a large portion of the single EHV-1 immediate early gene (0.78-0.83 and 0.95-1.00 map units) located in the IRs. Thus, these data and those previous studies (R. P. Baumann et al., 1984, J. Virol. 50, 13-21; R. P. Baumann, J. Staczek, and D. J. O-Callaghan, 1986, Virology 153, 188-200) indicate that the major subunits of the DI DNA molecule are comprised of selected sequences from the IRs component and a highly conserved short sequence located at the terminus of the L region of the standard viral genome.
Animals↗
SV40 DNA in a carrier system of human glioblastoma cells.
The state of the SV40 DNA in a stable carrier system of A172 human glioblastoma cells was examined by Southern blot hybridization analysis. At a sensitivity of 0.1 viral genome equivalents per cell, we detected only free, apparently nondefective, viral genomes. However, when we overexposed our autoradiograms or examined cloned cell populations, integrated viral sequences were observed. Furthermore, aberrant forms of free viral DNA were seen as well. Four clones, isolated at 15 weeks, produced T antigen and displayed enhanced saturation density and plating efficiency characteristic of SV40 transformation. None of these clones produced capsid proteins or infectious virus, even upon fusion with CV-1 cells, Viral DNA in the clones ranged from 0.5 to 50 equivalents per cell, on the average. Two of the Week-15 clones contained a similar (but not identical) predominant truncated SV40 sequence which was present both in a free state and integrated at a single major site in a reiterated head-to-tail array. These clones also contained other minor integrated sequences. Another Week-15 clone contained viral sequences integrated at two major sites as well as heterogeneous free DNA. Only free aberrant DNA was detected in the fourth Week-15 clone. Seven of eight clones isolated at 23 weeks produced no infectious virus or T antigen. No viral DNA was detected in those clones. The eighth clone did produce infectious virus and contained a predominance of free viral DNA. All of the clones were susceptible to superinfection with wild-type SV40, although less so than uninfected A172 cultures.
Antigens, Viral, Tumor↗
Adeno-associated viruses inhibit SV40 DNA amplification and replication of herpes simplex virus in SV40-transformed hamster cells.
Coinfection with HSV-1 and any of the three defective parvoviruses AAV-2, AAV-3, or AAV-5 reduces the HSV-1-induced amplification of SV40 DNA in the SV40-transformed hamster cell lines CO631 and Elona. Moreover, all three viruses significantly decrease HSV-1 replication. The effects are measurable to the same extent in both cell lines and are dependent on the quantity of AAV DNA molecules rather than on infectious AAV particles. It seems unlikely that the inhibitions are due to simple competition but result from complex interactions that involve the terminal sequences of AAV DNA.
Animals↗
Viral transcripts in cells infected with defective interfering particles of equine herpesvirus type 1.
Equine herpesvirus type 1 (EHV-1) preparations enriched in defective interfering particles (DIPs) have previously been demonstrated to mediate the coestablishment of persistent infection and oncogenic transformation in primary hamster embryo fibroblasts. In this study, it was demonstrated that infection of a rabbit kidney (RK) cell line with EHV-1 DIP-enriched preparations also results in the establishment of persistent infection. Viral transcription was characterized in RK cells infected with DIP-enriched stocks and compared to viral transcription in RK cells infected with standard (STD) EHV-1. During the first 8 hr of infection with the DIP-enriched EHV-1 preparation, viral DNA sequences which are conserved in the DIP genome were predominantly expressed. Thus, these transcripts originate from DNA sequences that contain the components of the defective genome which originates from DNA sequences mapping at 0.00-0.04 of the Long region terminus and within two portions of the Short region inverted repeats (IR), 0.78-0.79 and 0.83-0.865 of the internal IRs and 0.99-1.00 and 0.915-0.95 of the terminal IRs. The overwhelming majority of viral transcripts that were synthesized in the DIP-enriched infections appeared to correspond to transcripts expressed in STD infection as assessed by Northern hybridization analysis but the synthesis of transcripts originating from sequences not conserved in the defective genome was significantly delayed. However, some high molecular weight RNA species that were synthesized in STD infections were not detected in DIP-enriched infections. Studies utilizing metabolic inhibitors indicated that viral transcription in DIP-enriched infections, like that of STD cytocidal infection, is regulated in an immediate early, early and late manner.
Blotting, Northern↗
The expression, localization, and effect of a human interferon in plants.
The ORF II of Cauliflower mosaic virus (CaMV) DNA was replaced with the human IFN alpha D coding sequence to yield a stable CaMV strain designated Ca524i. Inoculation of turnip (Brassica rapa cv "Just Right") with strain Ca524i DNA excised from plasmid pCa524i resulted in the production of biologically active IFN alpha D in infected plants. This was also true for its mutant (Ca562i) where one of the CYS codons was deleted. IFN alpha D produced in planta did not hamper superinfection with a single-stranded (+) sense RNA plant virus, turnip yellow mosaic virus (TYMV). Antibody gold labeling techniques and electron microscopy of infected plants showed that IFN was localized in the CaMV inclusion bodies.
Cell Compartmentation↗
Interferon-induced expression of different genes is mediated by distinct regulatory pathways.
Interferons (IFNs) regulate the expression of multiple genes and the regulatory sequences associated with several of these genes have been identified. How cell-surface IFN receptors communicate with such regulatory elements is as yet unknown. We have characterized the IFN responses of a mutant murine cell line (Ltk-aprt-) which is unable to mount an antiviral response when treated with IFN-beta. In contrast to its inability to activate antiviral pathways in these cells, IFN-beta inhibits their growth to the same level as observed in their parental L-929 line which is fully responsive to IFN, suggesting that distinct pathways account for antiviral and cytostatic responses. In agreement with this, Northern blot and nuclear run-on analyses show that the induction of transcription of three distinct genes (2,5(A) synthetase, BS-I-150, and BS-II-4) is blocked in Ltk-aprt- cells whereas another gene (I-8) is activated normally. Our results show that the defective responses observed in this cell line are not due to a nonfunctional IFN-beta cell-surface receptor and suggest that multiple pathways exist between the receptor and upstream gene regulatory elements.
2',5'-Oligoadenylate Synthetase↗
Revertants of a mutant of vesicular stomatitis virus which has an aberrant polyadenylation activity and a temperature-sensitive transcriptase.
tsG16(l), a temperature-sensitive mutant of vesicular stomatitis virus, in vitro has at least three phenotypic differences from its parental wild-type (wt) virus due to mutation of the L gene. It was not known whether (i) the temperature-sensitivity of the transcriptase, (ii) the aberrant polyadenylation phenotype, and (iii) the extent of increased polyadenylation in response to S-adenosylhomocysteine (SAH) were associated with a single mutation. Spontaneous partial revertants were selected from tsG16(I) on the basis of the ability to form plaques at 34.7 degrees (35G16 revertants) or from 35G16 revertants on the basis of the ability to form plaques at 37 degrees (37G16 revertants). All six 35G16 revertants had fully (five) or partially (one) recovered the wt polyadenylation phenotype and the former five had also fully recovered the wt polyadenylation response to SAH. This suggested that a single mutation in tsG16(I) was probably associated with both of these phenotypes and also probably conferred the inability to grow at 34.7 degrees. None of the 35G16 revertants regained the wt phenotype for thermosensitivity of the transcriptase, although both of the 37G16 revertants did. This suggested that in vitro temperature-sensitivity of transcription by tsG16(I) might be due to a mutation different than the one affecting polyadenylation in the absence or presence of SAH.
Adenosine Monophosphate↗
Defective interfering particles: effects in modulating virus growth and persistence.
Defective interfering virus particles (DIP) frequently play an important part in viral persistence in vitro, and may in some instances modify a virus infection in vivo, causing attenuation or persistence of the infection. To explain certain aspects of the growth of these mutants in vitro, other factors have been invoked such as interferon, mutations in the wild-type virus or the infected cells, or other substances released by infected cells that attenuate the infection. We present here a simple model of the growth of DIP in vitro which shows that (a) the observed population dynamics of DIP can readily be explained without invoking such extrinsic factors; (b) the initial multiplicity of infection of DIP is the principal determinant of the outcome of infection in both single- and repeated-passage cultures; and (c) in a long-term culture in vitro, the criterion used to decide the time of virus passage directly determines how long the standard virus, DIP, and cells survive. This model may be used with minor modifications to predict the behavior in vitro of other mutant viruses with a dominantly interfering phenotype.
Biological Evolution↗
Rescue of a Sendai virus DI genome by other parainfluenza viruses: implications for genome replication.
Using a defective interfering Sendai virus stock (DIH4) freed of nondefective helper virus, we found that the closely related parainfluenza viruses 1 and 3 could substitute for the Sendai virus helper in replicating DIH4, creating chimeric nucleocapsids. The morbillivirus measles and the rhabdovirus VSV could not substitute. When DIH4 is incubated intracellularly for 5 days in the absence of help, the ability of PIV3 to rescue DIH4 at this time depended on fresh Sendai virus polymerase. The PIV3 polymerase apparently can only copy the chimeric template, but not that wrapped in the homologous Sendai NP protein. These results suggest that the cis-acting RNA sequences important for genome replication, e.g., the promoter and the encapsidation site, have been conserved among these viruses, but that the interactions between the polymerase and the template protein NP are unique for each virus.
Animals↗
Biologically active cymbidium ringspot virus satellite RNA in transgenic plants suppresses accumulation of DI RNA.
A full-length DNA copy of cymbidium ringspot virus (CyRSV) satellite RNA was cloned downstream of the bacteriophage T7 RNA polymerase promoter. In vitro transcripts were biologically active in plants when coinoculated with the helper virus or its RNA. Although the transcripts contained 7 or 29 extra nucleotides at the 3' end, the proper 3' terminus was restored in the satRNA progeny. Full-length cDNA clones of CyRSV satRNA under the control of the cauliflower mosaic virus 35S promoter and terminator were used to transform Nicotiana benthamiana plants. Integration of CyRSV satRNA sequence in the plant genome was tested by PCR amplification of DNA extracts from transformed plants and by detection of satRNA-related transcripts in total RNA extracts. Inoculation of transgenic plants with the helper virus induced replication of satRNA of the same size as the native molecule. Sequence analysis of the satRNA progeny showed that it was identical to natural CyRSV satRNA. Infected transgenic plants were not protected from apical necrosis and death by the presence of satRNA sequences. Rather, replication of satRNA was found to suppress accumulation of defective interfering RNA, which acts in the absence of satRNA as an attenuator of virus replication and disease.
Base Sequence↗