- Volume 74, Issue 6, 1993
Volume 74, Issue 6, 1993
- Animal
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Prophylactic and therapeutic vaccination against a mucosal papillomavirus
Papillomaviruses are ubiquitous DNA viruses affecting humans and animals and causing a variety of tumours of mucosal and cutaneous epithelia. Some of these lesions, particularly those affecting mucosal epithelia, can progress to squamous cell carcinomas. Prevention or cure of viral infection would ultimately lead to a decrease in the incidence of papillomavirus-associated cancers. Using recombinant proteins, we have developed prophylactic and therapeutic vaccines against bovine papillomavirus type 4, a mucosal papillomavirus implicated in cancer of the alimentary canal in cattle; similar possibilities exist for the human mucosal papillomaviruses.
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Characterization of human keratinocytes transformed by high risk human papillomavirus types 16 or 18 and herpes simplex virus type 2
Recent reports implicate two DNA tumour viruses, herpes simplex virus type 2 (HSV-2) and human papillomavirus types 16 or 18 (HPV-16 and -18), in the pathogenesis of cervical cancer. Previous studies have indicated that primary human fibroblasts transfected with HPV-16 and HSV-2 morphological transforming region III (mtr III) are more aneuploid than fibroblasts immortalized with HPV-16 and that HSV-2 DNA sequences are retained in transformed cells. Since HSV-2 and HPV typically infect cells of epithelial origin, the interactions of these viruses with respect to morphological transformation were examined in human keratinocytes. HPV-16- or HPV-18-immortalized keratinocytes (FEPL and FEA cells, respectively) were transfected with fragments derived from HSV-2 mtr III. When compared to their normal counterparts, FEPL cells and FEA cells transfected with mtr III fragments grew to higher saturation densities and were morphologically transformed. FEPL cells transformed by HSV-2 were capable of growth in soft agar and, when injected into nu/nu mice, lesions developed at the site of injection. Histological examination of the lesions revealed a benign mass which was composed of squamous epithelial cells that were producing keratin. In contrast, immortalized keratinocytes (FEPL or FEA) or FEA cells transfected with HSV-2 did not produce these lesions. These observations suggest that sequences within mtr III can alter the growth properties of human keratinocytes immortalized by HPV-16 or HPV-18.
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Herpes simplex virions interfere with the expression of human papillomavirus type 18 genes
More LessPapillomaviruses are believed to play an important role in the development of genital carcinoma. Herpes simplex virus (HSV) has been proposed as a cofactor. Here we show that HSV-1 interferes with the expression of human papillomavirus (HPV-18) genes in HeLa cells by reducing the amount of papillomaviral mRNA. By 7 h after HSV-1 infection, expression was reduced by a factor of 50. Experiments with the HSV-1 mutant tsK, with cycloheximide and with u.v.-irradiated virus indicated that the reduction was not due to newly made immediate early, early or late HSV-1 gene products but rather to a component of the virion. Replication of the HSV-1 is therefore not required for the reduction of the HPV-18 mRNA. The HSV-1 strain 17+, which has only a very weak virion host shutoff function, still specifically decreased the level of the papillomaviral mRNA suggesting that either the decrease is due to a new HSV-1 function or that the HPV-18 mRNA is especially sensitive to the low residual host shutoff activity of strain 17+. Experiments with the virus 17(41-), in which the host shutoff function is inactivated by a mutation in the UL41 gene, showed clearly that it is the host shutoff function which is responsible. The papillomaviral mRNA therefore appears to be hypersensitive to the herpesvirus host shutoff function.
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Characterization of the UL10 gene product of herpes simplex virus type 1 and investigation of its role in vivo
More LessOn the basis of predicted amino acid sequence characteristics, herpes simplex virus type 1 gene UL10 is thought likely to encode a membrane protein with eight potential transmembrane regions. Previously, a protein with an apparent M r 47 000 on SDS-PAGE was identified as a product of this gene. Here we have further characterized this protein, and show that it is modified by N-linked glycosylation, associates with membranes from infected cells, and is a component of the virus particle. It is not essential for virus growth in tissue culture. To investigate its role in vivo a deletion mutant lacking the majority of the UL10 open reading frame was constructed (UL10-del). The in vitro growth properties of this virus were consistent with previous studies; it grew to give slightly lower yields than wild-type and revertant viruses, and had no apparent temperature-sensitive or host range phenotype. In vivo, in a mouse model, UL10-del was capable of establishing a latent infection, although it was impaired for growth at the periphery, and for spread to and/or growth within the nervous system relative to wild-type or revertant viruses.
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Neurons containing latency-associated transcripts are numerous and widespread in dorsal root ganglia following footpad inoculation of mice with herpes simplex virus type 1 mutant in1814
More LessThe herpes simplex virus type 1 (HSV-1) mutant in1814 lacks the ability to trans-activate immediate early gene transcription and enter lytic replication but it can establish and reactivate from latency. We therefore investigated the number of neurons that expressed latency-associated transcripts (LATs) in animals latently infected with in1814, the rescued revertant (1814R), or wild-type (wt) HSV-1. The percentage of LAT+ neurons increased with increasing doses of each of the viruses. After inoculation of equal amounts of infectious virus many more LAT+ neurons were observed in animals infected with in1814 than with 1814R or wt HSV-1. Whereas the LAT+ neurons in animals infected with 1814R or wt HSV-1 were largely confined to lumbar dorsal root ganglia (DRG) L4/L5/L6 (those which innervate the lower leg), in animals infected with in1814 they were also present in DRG not directly involved with such innervation (thoracic 12 and 13, L1, L2 and L3). We concluded that the large number of LAT+ neurons observed with in1814 was related to the high particle numbers in the inoculum and that spread of virus was related to limited replication as well as to the low neurovirulence of in1814. This spread was not unique to in1814 but when it occurred with more virulent viruses such as 1814R or wt HSV-1, it resulted in the death of the host.
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Reactivation in vivo and in vitro of herpes simplex virus from mouse dorsal root ganglia which contain different levels of latency-associated transcripts
More LessIn the dorsal root ganglia (DRG) of mice latently infected with the herpes simplex virus type 1 mutant in1814, there are more neurons that contain latency-associated transcripts (LATs) than in DRG of mice infected with a dose of equal infectivity of either a revertant or a wild-type virus. We investigated whether higher levels of LAT+ neurons resulted in more extensive reactivation either in vivo following neurectomy of the sciatic nerve or in vitro after explantation into culture. Neurectomy appeared to induce expression of immediate early 1 mRNA (IE1mRNA) in neurons of mice latently infected with each of three viruses. However IE1mRNA was detected in no more than 0.25% of the neurons of DRG from animals 2 to 4 days after neurectomy, irrespective of the percentage of LAT+ neurons present. Of the 22 neurons shown to express IE1mRNA, none expressed LATs also. However the lack of expression of viral antigen and the absence of a reduced potential for reactivation on explantation suggested that neurectomy had not induced full reactivation involving lytic replication leading to the death of the latently infected neurons. When DRG were explanted into culture, the distribution of the frequency of reactivation was similar to the distribution of DRG that contained LAT+ neurons. The presence of a high proportion of LAT+ neurons was not directly associated with earlier detection of reactivation but such experiments cannot be regarded as quantitative. We therefore concluded that neurectomy did not result in a reduced reactivation potential as described by others and that the frequency of expression of IE1mRNA following neurectomy did not correlate with the number of LAT+ neurons present.
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Identification of a DNA-binding protein of human herpesvirus 6, a putative DNA polymerase stimulatory factor
A 41K early nuclear antigen (p41), expressed in human herpesvirus type 6 (HHV-6)-infected T cells, was cloned by screening a cDNA expression library with the anti-p41 monoclonal antibody (MAb) C5. When expressed in mammalian cells, the cloned p41 protein comigrated with the authentic p41 protein from HHV-6-infected cells and localized to the nucleus. HHV-6 p41 shares 44% sequence identity with the human cytomegalovirus (HCMV) DNA-binding protein, ICP36 (UL44 gene product); p41 binds to ssDNA with the same apparent affinity as ICP36. Since ICP36 has recently been shown to be an HCMV DNA polymerase-associated stimulatory factor, a similar function is suggested for p41.
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Kinetic studies of the predicted substrate-binding site of varicella-zoster virus thymidine kinase
More LessTo investigate the mechanism of kinetic action and substrate recognition of varicella-zoster virus (VZV) thymidine kinase (TK), we designed and isolated a site-directed mutant VZV TK which has double amino acid substitutions, 136threonine to leucine and 137isoleucine to leucine (SDM TK). This mutant was designed to alter the substrate-binding site of the VZV TK to duplicate that of the herpes simplex virus type 2 enzyme. Kinetic studies of the activity of wild-type TK indicated that the binding order of ATP and thymidine is random and that wild-type VZV TK possessed high thymidylate kinase (TM-K) activity. The sensitivity of VZV TK to bisubstrate analogues, dinucleotides of adenosine and thymidine, showed that the optimum distance between the ATP- and substrate-binding sites is two phosphoryl groups greater than with the natural substrate for TK activity. SDM TK lost deoxycytidine kinase activity and had reduced TK and TM-K activities. Inhibition studies on both WT and SDM TK by 5-halogenovinyluridine analogues and their 5′ monophosphate derivatives revealed that amino acids at positions 136 and 137 are involved in substrate binding, probably through a role in the formation of the binding pocket for bulky substrates.
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Nucleotide sequence and transcriptional analysis of the p10 gene of Spodoptera exigua nuclear polyhedrosis virus
The p10 gene of Spodoptera exigua multiple nuclear polyhedrosis virus (SeMNPV) was localized on the XbaI fragment H (5.1 kb) of the physical map of the viral genome. The coding sequence of the SeMNPV p10 gene is 264 nucleotides (nt) long corresponding to a predicted protein of 88 amino acids with an M HF of 9607. The SeMNPV p10 protein showed only limited amino acid identity (39% and 26%, respectively) to those of Orgyia pseudotsugata MNPV (OpMNPV) and Autographa californica MNPV (AcMNPV) and thus appears less conserved than other viral proteins. The SeMNPV p10 gene was expressed by a transcript of approximately 450 nt, which started in the conserved baculovirus late gene promoter motif TAAG. The leader of the SeMNPV p10 transcript was AT-rich (92%) and at 36 nt was the shortest leader of all baculovirus major late genes reported so far. The SeMPNV p10 transcript terminated 6 nt downstream from a putative poly(A) signal sequence (AATAAA); the latter was 61 nt downstream of the translational stop codon TAA. Upstream and downstream of the p10 gene, partial putative ORFs were found that showed significant amino acid sequence identity to the baculovirus p26 and p74 proteins. It is concluded that the region of SeMNPV DNA containing the p10 gene is collinear with the corresponding regions in the AcMNPV and OpMNPV genomes.
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Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie
More LessPrP glycoprotein gene polymorphisms were examined in Swaledale sheep affected by natural scrapie, in healthy sheep and in Swaledales selected for low susceptibility to scrapie. The three groups differed significantly in frequencies of PrP genotypes detected by the restriction enzymes EcoRI, HindIII and BspHI, the latter being indicative of a PrP protein amino acid difference at codon 136. These frequency differences were confirmed in a single-flock study and present good evidence that scrapie susceptibility and resistance are associated with PrP gene variants in Swaledale sheep.
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Comparison of serum antibody reactivities to a conformational and to linear antigenic sites in the external envelope glycoprotein of simian immunodeficiency virus (SIVmac) induced by infection and vaccination
More LessForty-six overlapping peptides (20-mers) representing the amino acid sequence of the external envelope glycoprotein of simian immunodeficiency virus (SIVmac; 32H isolate) were used to investigate linear antigenic sites recognized by antibodies in sera from SIV-infected rhesus macaques and in animals vaccinated with formalin-inactivated SIV. The reactivity to a discontinuous antigenic site as defined by a neutralizing monoclonal antibody was measured by competition assay. The majority of infected macaques recognized three linear antigenic determinants within the V1, V3 and C5 regions of the external glycoprotein. Animals infected with virus derived from the molecular clone SIVmac 32H (pJ5) showed broader reactivity to peptides with half of these animals having antibodies to the V2 region in addition to the V1, V3 and C5 regions. The majority of animals produced antibodies in response to the discontinuous epitope although these responses were weaker in animals infected with molecularly cloned virus. Seven of eight animals given vaccine in syntex adjuvant formulation (saf-1) produced antibodies in response to the discontinuous epitope and all reacted with peptides from the V1, V2 and V3 regions but only half recognized the C5 region. Animals receiving vaccine in alum adjuvant generally showed weaker responses to the discontinuous and linear determinants than those receiving saf-1 adjuvanted vaccine.
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Simian immunodeficiency virus (SIVmac251) membrane lipid mixing with human CD4+ and CD4- cell lines in vitro does not necessarily result in internalization of the viral core proteins and productive infection
More LessThe cell binding site of simian immunodeficiency virus (SIV) is believed to be the CD4 molecule. Several CD4+ cell lines are, however, resistant to infection by SIVmac251 in vitro and additional cell membrane molecules have been implicated in SIVmac251 entry. We investigated the binding, envelope fusion and entry of the viral core proteins (p27) of SIVmac251 into two human CD4+ cell lines (H9 and Sup-T1) which are infectible, and one CD4+ (A3.01) and two CD4- cell lines (K562 and Raji) that are resistant to infection. The fusion of the viral and cellular membranes was monitored by a fluorescence assay for lipid mixing. Cell entry of the viral core was evaluated following virus-cell incubation and cell surface trypsinization. We found that SIVmac251 can bind to and fuse (membrane lipid mixing) in a temperature-dependent but pH-independent fashion with CD4+ and CD4- human-derived cell lines. In contrast, lipid mixing with CD4 expressing EL-4 mouse T cells or Mv-1-lu mink lung fibroblasts was absent or limited, suggesting that certain components of human cell membranes in addition to CD4 are involved in SIVmac envelope-cell fusion. Lipid mixing with the human cells was inhibited partially by soluble CD4. Anti-CD4 antibodies inhibited the lipid inter-mixing with H9, but not with Raji cells, whereas neutralizing anti-SIVmac sera inhibited fusion with both CD4+ and CD4- cells. Out of the five human cell lines tested, efficient entry of p27 and productive infection took place only with H9 and Sup-T1 cells. In these two cases, the amounts of p27 internalized during virus-cell fusion correlated with the extent of infection.
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Analysis of the stimulation of reporter gene expression by the σ3 protein of reovirus in co-transfected cells
More LessThe stimulation of reporter gene expression following co-transfection with the S4 gene of mammalian reoviruses was analysed. The σ3 protein of type 3 reovirus gave a five- to eightfold increase in expression of chloramphenicol acetyltransferase and β-galactosidase but this was found to be dependent upon the nature of the promoter being used to drive reporter gene expression. The σ3 protein of reovirus type 1 failed to stimulate reporter gene expression under any of the conditions used. Hybrid constructs between the S4 genes of reoviruses type 1 and 3 were used to map the stimulation characteristic to the carboxy-terminal third of the gene. Analysis of the level of σ3 protein accumulation in transfected cells showed that the reovirus type 3 protein accumulated to a much higher level than that of reovirus type 1. Using the hybrid gene constructs this higher level of protein accumulation was shown to co-segregate with the ability to stimulate reporter gene expression.
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Enhancement of phospholipase activity during poliovirus infection
More LessInfection of human cells with poliovirus leads to modification of phospholipase activity. Phospholipase C, which generates inositol triphosphate, is stimulated, whereas the activation of phospholipase A2 by the calcium ionophore A23187 is inhibited. Analysis of phospholipid moieties in media of HeLa cells infected with poliovirus indicates that the release of fatty acids is not enhanced during infection, suggesting that phospholipase A1 and A2 activities are not stimulated. The release of choline into the medium is significantly higher 3 h after infection, indicating that a phospholipase that has phosphatidylcholine as its substrate becomes activated. This activation requires viral gene expression because inhibitors of poliovirus gene expression added at the beginning of infection block choline release, but continuous viral protein synthesis is not required. Choline and phosphorylcholine are released into the medium, but the pools of both are gradually depleted in poliovirus-infected cells, perhaps as a consequence of their release into the medium and the increased synthesis of phospholipids that takes place in poliovirus-infected cells. Inhibitors of phospholipase activity such as mepacrine, zinc or cadmium ions significantly reduce this increased release of choline from poliovirus-infected cells. Labelling of cells with [3H]phosphatidylcholine suggests that the choline released from infected cells comes, at least in part, from the hydrolysis of this compound. These results indicate that, in addition to the activation of the phospholipase C which hydrolyses phosphatidylinositol in poliovirus-infected cells, a phospholipase C that acts on a phosphatidylcholine is also activated.
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Measles virus haemagglutinin induces down-regulation of gp57/67, a molecule involved in virus binding
More LessA surface glycoprotein (gp57/67) was previously shown to be involved in measles virus (MV) binding and characterized in our laboratory. Here, we described down-regulation of cell surface gp57/67 after infection with MV. This effect is specific for MV since cells infected with canine distemper virus, closely related to MV, did not down-regulate gp57/67. The decrease in cell surface gp57/67 correlated with expression of MV glycoproteins and more particularly with the expression of MV haemaggluttinin (MV-H). Indeed, expression of MV-H after infection with a vaccinia virus recombinant coding for MV-H was necessary and sufficient to induce down-regulation of gp57/67. Kinetics of cell surface expression of MV-H and gp57/67 showed that the degree of down-regulation was correlated with the amount of MV-H expressed by infected cells. Experiments using antibody-prelabelled gp57/67 and indirect immunofluorescence microscopy allowed us to follow the fate of gp57/67 and showed that down-regulation was occurring by rapid internalization of gp57/67 from the cell surface. These results provide additional evidence that the gp57/67 molecule is closely associated with the pathway of MV infection and also reveal a phenomenon which may be related to viral pathogenesis and persistence.
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Analysis of pathotype-specific structural features and cleavage activation of Newcastle disease virus membrane glycoproteins using antipeptide antibodies
More LessPeptides were synthesized, that correspond to cleaved and trimmed carboxyl termini of the F2 polypeptide regions of fusion (F) protein precursors (F0 proteins) in four different strains of Newcastle disease virus (NDV). These peptides differed only within the four carboxylterminal residues and represent F2 polypeptides of virulent (AV), low-virulence (EG) and avirulent (V4 and WA) pathotypes of NDV. Polyclonal rabbit antisera against each peptide reacted with their corresponding monomeric F2 polypeptides and F protein oligomers as analysed by immunoblotting of egg-propagated virions. Bidirectional cross-reactivity was observed between V4 and EG antisera and F2 polypeptides which differ only by a single variation of lysine and arginine at position 3 from their carboxyl termini. The other two antisera (AV and WA) were specific for their corresponding F2 polypeptides. All of these antisera were shown to react in a strain-specific manner with intact egg-propagated virions in an ELISA. A previously described antiserum, designed to target the haemagglutinin-neuraminidase (HN) protein precursor (HN0 protein) of avirulent strains of NDV, has been shown to be specific for residual HN0 protein of avirulent virions propagated in embryonated chicken eggs. Whereas the antiserum targeted at the carboxyl terminus of the V4 F2 polypeptide did not react with F0 proteins of cell culture-propagated strains in immunoblotting, antipeptide antibodies targeted at another region of the F2 polypeptide and a segment of the F1 polypeptide did react with the F0 protein from infected cells. These data are consistent with inclusion of the terminal carboxylate of the F2 polypeptides in the recognition determinants of the antibodies targeted at the carboxyl terminus of the V4 F2 polypeptide. The antisera described herein are ideally suited to rapid immunochemical pathotyping of NDV isolates and immunochemical characterization of the sites of intracellular cleavage activation of F0 and HN0 proteins and may be useful for defining interactions involved in F protein folding.
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Typing of hepatitis C virus isolates and characterization of new subtypes using a line probe assay
A reverse-hybridization assay, the line probe assay (LiPA), based on variations found in the 5′ untranslated regions of the different hepatitis C virus (HCV) genotypes was developed, permitting simple and fast determination of four HCV genotypes and their subtypes. Using this assay, 61 PCR-positive Brazilian HCV sera were typed. Of the sera, 33% had a type 1 HCV infection, 38% had type 1b (related to HCV-J), 1.5% had type 2a (related to HC-J6), 24.5% had type 3 (related to E-b1 and HCV-T), and 3% of the sera were co-infected. This assay format was further evaluated using 13 sera from Belgium and the Netherlands, and all of these could be classified. Two pools of Japanese sera were classified as either type 2a or were co-infected with types 1b and 2a, but no type 2b sequences were detected. Another eight PCR-positive sera were obtained from Burundi and Gabon. The sequence of the 5′ untranslated region of these African viruses was strongly divergent from the three previously described types. Therefore, these isolates were tentatively classified as type 4. These and some of the other non-type 1 sera often demonstrated weaker reactivities than type 1 isolates in currently used second generation antibody confirmation assays.
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Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome
We have expressed the full-length coding region and selected domains of the hepatitis C virus (HCV) cDNA in mammalian cells by transfection. Using HCV antibody-positive human sera and monospecific antibodies the proteins encoded by the putative structural and non-structural regions of the open reading frame of HCV were identified as core (p22), E1 (gp32–35), E2 (gp68–72), NS2 (p23), NS3 (p72), NS4a and b (p10 and p27) and NS5a and b (p56 and p70). We have also defined the subcellular localizations of the HCV proteins using indirect immunofluorescence assays.
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Expression of non-conserved regions of the S genome segments of three hantaviruses: evaluation of the expressed polypeptides for diagnosis of haemorrhagic fever with renal syndrome
More LessHaemorrhagic fever with renal syndrome (HFRS) is a serious and often fatal disease caused by viruses in the Hantavirus genus of the family Bunyaviridae. We expressed the entire coding region of the small (S) genome segments of three serologically distinct hantaviruses as soluble proteins in Escherichia coli and evaluated the expressed nucleocapsid proteins (NPs) as antigens for diagnosis of HFRS. We also prepared novel diagnostic antigens by expressing truncated genes from which we deleted amino acid coding regions that were highly conserved among the three viruses. These antigens were analysed for their potential to detect and differentiate between antisera to various hantaviruses by ELISA. ELISA results obtained with HFRS patient sera or with sera from naturally or experimentally infected animals indicate that homologous antigens and antisera reacted to high titre. The truncated NPs were more specific than the complete NPs in distinguishing between possible aetiological agents of HFRS. Our findings demonstrate that prokaryotic expression of portions of the NPs of specific hantaviruses can be used to generate, readily and efficiently, large quantities of antigen that is both sensitive and specific in diagnostic assays for HFRS.
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Encapsidation of a recombinant LuIII parvovirus genome by H1 virus and the fibrotropic or lymphotropic strains of minute virus of mice
More LessWe previously constructed a recombinant LuIII parvovirus genome lacking viral coding sequences and used it to generate luciferase-transducing virions, by co-transfection of cells with a helper plasmid expressing LuIII viral proteins. Here, we describe similar cotransfections using alternative, replication-defective helpers encoding the non-structural and capsid proteins of parvovirus H1, or of either the fibrotropic or lymphotropic parvovirus strain of minute virus of mice [MVM(p) or MVM(i)]. Each contransfection generated transducing virus which directed luciferase expression after infection of HeLa cells. The transducing activity of virus produced using either LuIII or H1 helper plasmids could be specifically neutralized by antiserum raised against the corresponding infectious virus. When the recombinant LuIII parvovirus was pseudotyped with MVM(p) or MVM(i), the resulting virions efficiently expressed luciferase after infection in human or murine cells known to be permissive for both MVM strains. The MVM(p) pseudotyped virus also expressed this reporter efficiently when infected into the murine A9 fibroblast line. In contrast, the recombinant virus generated with an MVM(i) helper gave luciferase expression that was barely detectable after infection of A9 cells which are highly restrictive for MVM(i) productive infection. These results support the notion that the allotropic determinant of these MVM strains functions through their capsid proteins. Pseudotyping of recombinant parvovirus genomes should be useful in controlling their host range as vectors, and in studying mechanisms influencing the permissiveness of parvovirus infections.
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