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PubMed1991

Defective interfering particles of human parainfluenza virus type 3 are associated with persistent infection in cell culture.

CV-1 cell lines persistently infected with human parainfluenza virus type 3 (HPF3) contain one or more distinct subgenomic RNAs in addition to standard viral genomes. These RNAs are shown to be the genomes of defective-interfering (DI) particles of the virus; they are present in particles in the culture fluid, and they interfere with the growth of wild-type virus. Removal of the particles from the culture fluid by ultracentrifugation yields a supernatant fluid free from inhibitory activity, demonstrating that the anti-viral effect is not mediated by soluble factors. A role for the DI particles in persistence of HPF3 is considered.

Capsid↗
PubMed1998

Studies of persistent infection by Chlamydia trachomatis serovar K in TPA-differentiated U937 cells and the role of IFN-gamma.

Inoculation of phorbol ester-differentiated U937 cells as a model for human macrophages with Chlamydia trachomatis of the urogenital serovar K resulted in a persistent infection, with maximal growth at day 7, until day 10 post-infection. At these times inclusion bodies were present in 0.5-2% of the cells. Typical inclusion bodies containing elementary bodies and reticulate bodies were observed by electron microscopy. Furthermore, single chlamydial particles resembling atypical elementary or intermediate bodies were identified in the cytoplasm in > 80% of the host cells. IFN-gamma exerts antichlamydial activity in epithelial and fibroblastoid cells, but the infection of U937 cells by C. trachomatis was not affected by IFN-gamma. The activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) was not detected in untreated or in IFN-gamma-treated or chlamydiae-infected or mock-infected U937 cells. The presence of atypical persisting chlamydiae and the lack of IDO expression in U937 cells indicates that the development of these atypical bacteria is independent from IFN-gamma-mediated tryptophan deprivation and other IFN-gamma-mediated effects. Evaluation of persistently infected cells revealed that the expression of the chlamydial major outer-membrane protein, heat-shock protein (hsp60) and lipopolysaccharide (LPS) antigens was not significantly altered in the course of the culture. An intense staining of the LPS on the surface of the host cells was demonstrated by immunofluorescence. The data show that phorbol ester-differentiated U937 cells restrict chlamydial growth strongly but not completely through a mechanism distinct from IDO-mediated tryptophan deprivation. The mechanisms of persistence of chlamydiae in monocytes, which differ considerably from those described for other cells, require further investigation.

Antigens, Bacterial↗
PubMed1988

Coevolution of cells and viruses in a persistent infection of foot-and-mouth disease virus in cell culture.

Virus and cells evolve during serial passage of cloned BHK-21 cells persistently infected with foot-and-mouth disease virus (FMDV). These carrier cells, termed C1-BHK-Rc1 (J.C. de la Torre, M. Dávila, F. Sobrino, J. Ortín, and E. Domingo, Virology 145:24-35, 1985), become constitutively resistant to the parental FMDV C-S8c1. Curing of late-passage C1-BHK-Rc1 cells of FMDV by ribavirin treatment (J.C. de la Torre, B. Alarcón, E. Martínez-Salas, L. Carrasco, and E. Domingo, J. Virol. 61:233-235, 1987) did not restore sensitivity to FMDV C-S8c1. The resistance of C1-BHK-Rc1 cells to FMDV C-S8c1 was not due to an impairment of attachment, penetration, or uncoating of the particles but to some intracellular block that resulted in a 100-fold decrease in the amount of FMDV RNA in the infected cells. FMDV R59, the virus isolated from late-passage carrier cells, partly overcame the cellular block and was more cytolytic than FMDV C-S8c1 for BHK-21 cells. Sequencing of the VP1 gene from nine viral clones from C1-BHK-Rc1 cells showed genetic heterogeneity of 5 X 10(-4) substitutions per nucleotide. Mutations were sequentially fixed during persistence. In addition to resistance to FMDV C-S8c1, C1-BHK-Rc1 cells showed a characteristic round cell morphology, and compared with BHK-21 cells, they grew faster in liquid culture, were less subject to contact inhibition of growth, and had an increased ability to form colonies in semisolid agar. Reconstitution of a persistent infection was readily attained with late-passage C1-BHK-Rc1 cells and FMDV C-S8c1 or FMDV R59. The results suggest that coevolution of BHK-21 cells and FMDV contributes to the maintenance of persistence in cell culture.

Animals↗
PubMed1981

Induction of persistent infection in mice and oncogenic transformation of mouse macrophages with infectious bovine rhinotracheitis virus.

Infectious bovine rhinotracheitis virus (IBRV) established long-term persistent infection in intracerebrally inoculated athymic nude mice. After intraperitoneal injection into outbred mice, virus was isolated for only 3 days from spleens and livers. In vitro inoculation of outbred mouse spleen fragments with IBRV resulted in persistent infection and subsequent transformation of spleen macrophages. The IBRV-specific membrane and intracellular antigens were detected by indirect immunofluorescence techniques in transformed cells in early in vitro passages. The presence of IBRV genetic formation was confirmed by in situ hybridization. The IBRV-transformed mouse macrophages induced fibrosarcomas and cystic tumors in athymic nude mice. Infective virus could not be rescued from transformed cells by cocultivation with rabbit kidney cells, treatment with iododeoxyuridine, or ultraviolet irradiation.

Animals↗
PubMed1976

Relationship between establishment of persistent infection of haemagglutinating virus of Japan and the properties of the virus.

The infectious virus (HVJ-pi) obtained from BHK cells persistently infected with haemagglutinating virus of Japan was found to be temperature-sensitive as well as causing little or no cytopathic effect (c.p.e.) and leading to establishment of carrier cultures in several cell lines at both permissive (32 degrees C) and non-permissive (38 degrees C) temperature. In order to obtain information about the role of HVJ-pi in the establishment of persistent infection, comparative studies were made of some phenotypic properties of HVJ-pi and HVJ-38 which was obtained by passing wild-type HVJ in eggs at 38 degrees C and was proved to be highly cytopathic. HVJ-pi differed from HVJ-38 in (1) temperature sensitivity in its ability to produce virus progeny, (2) infectivity for embryonated eggs, (3) neuraminidase activity, (4) the thermal stability of HA and neuraminidase activity, and (5) the polypeptide composition of BHK-grown viruses. B cells infected with HVJ-pi release haemagglutinin more efficiently, and less HA was accumulated on the cell membrane. In considering these results, it was concluded that the difference of envelope proteins might be involved in the striking difference in c.p.e. between HJV-pi and HVJ-38.

Cell Line↗
PubMed1987

Persistent infection of chimpanzees with human immunodeficiency virus: serological responses and properties of reisolated viruses.

Persistent infection by human immunodeficiency virus (HIV-1) in the chimpanzee may be valuable for immunopathologic and potential vaccine evaluation. Two HIV strains, the tissue culture-derived human T-cell lymphotropic virus type IIIB (HTLV-IIIB) and in vivo serially passaged lymphadenopathy-associated virus type 1 (LAV-1), were injected intravenously into chimpanzees. Two animals received HTLV-IIIB as either virus-infected H9 cells or cell-free virus. A third animal received chimpanzee-passaged LAV-1. Evaluation of their sera for virus-specific serologic changes, including neutralizations, was done during a 2-year period. During this period all animals had persistently high titers of antibodies to viral core and envelope antigens. All three animals developed a progressively increasing type-specific neutralizing LAV-1 versus HTLV-IIIB antibody titer during the 2-year observation period which broadened in specificity to include HTLV-HIRF, HTLV-IIIMN, and HTLV-IIICC after 6 to 12 months. The antibody titers against both viruses were still increasing by 2 years after experimental virus inoculation. Sera from all animals were capable of neutralizing both homologously and heterologously reisolated virus from chimpanzees. A slightly more rapid type-specific neutralizing response was noted for the animal receiving HTLV-IIIB-infected cells compared with that for cell-free HTLV-IIIB. Sera from all persistently infected chimpanzees were capable of mediating group-specific antibody-mediated complement-dependent cytolysis of HIV-infected cells derived from all isolates tested. Viruses reisolated from all three animals at 20 months after inoculation revealed very similar peptide maps of their respective envelope gp120s, as determined by two-dimensional chymotrypsin oligopeptide analysis. One peptide, however, from the original HTLV-IIIB-inoculated virus was deleted in viruses from all three animals, and in addition, we noted the appearance of a new or modified peptide which was common to LAV-1 as well as to HTLV-IIIB reisolated from infected chimpanzees. It thus appears that a group-specific neutralizing antibody response as well as a group-specific cytotoxic response can develop in chimpanzees after an inoculation of a single HIV variant. This finding suggests that a common, less immunodominant determinant(s) is present on a single HIV strain which could induce group-specific antibodies during viral infection and replication. The identification of this group-specific epitope and the induction of analogous immunity may be relevant to vaccine development against human acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Relation of HVJ (Sendai virus) production to cell growth phase in persistently infected mouse 3T3 cells.

Using 3T3 mouse fibroblasts persistently infected with temperature-sensitive HVJ (3T3-HVJ pi), the relationship between production of HVJ and cell growth was investigated. In these cells the highest virus release into the culture media occurred from 24 to 48 hours after seeding. The release gradually decreased as the cultures approached confluency, at which time it was reduced below 1-2 per cent of that on day 2 in parallel with the decrease of both cellular DNA and RNA synthesis rates. Comparative examination in growing and resting HVJ carrier 3T3 cells showed that amounts of nucleocapsids and rate of viral structural protein synthesis in the latter phase was reduced to 4-5 per cent of those in the former phase. In addition, viral replication and transcription rates in the resting phase were found to be suppressed to 8-9 per cent of levels detected in the growing phase. These results suggest that the reduced virus production in the resting HVJ carrier cells may be mainly due to the suppression of viral RNA synthesis.

Animals↗
PubMed1976

Mononuclear cell fraction carrying Herpesvirus saimiri in persistently infected squirrel monkeys.

Circulating lymphocytes from squirrel monkeys persistently infected with Herpesvirus saimiri (HVS) were separated into B- and T-lymphocyte fractions by a rosette-enrichment technique. HVS was isolated only from lymphocyte fractions forming rosettes or from unseparated lymphocytes; this indicated that T-lymphocytes were the target cells for HVS in the natural host, squirrel monkeys.

Animals↗
PubMed1988

Persistent infection of YAC-1 cells by coxsackievirus B3.

Persistent infection (PI) of YAC-1 cells by coxsackievirus B3 (CBV-3) was characterized. CBV-3 PIs were maintained for 7 months or more, although in two other cases cells were cured of virus at 6 and 6.5 months of PI. The titre of infectious virus peaked during the first week of the infection and then gradually decreased. The proportion of cells producing infectious centres increased to 100% by 48 h after infection, remained at that level up to the seventh day, and then rapidly decreased. Susceptibility to PI by CBV-3 varied widely among 40 clones from uninfected YAC-1 cells as judged by the yield of infectious virus at 6 weeks post-infection. None of the clones was completely lysed by the virus. Clones were not obtained from cells infected for 2 or 7 days. Of six clones obtained from cells infected for 14 days and 24 clones from cells infected for 6 weeks, none was producing virus and all were resistant to reinfection by CBV-3. Six of the clones were serially subcultured and all remained resistant for as long as they were maintained (5 months). During the course of the PI, viral variants which produced smaller plaques and required a longer incubation period for the development of visible plaques replaced the original viral population. Thus the PI involved a carrier culture with a large proportion of resistant cells. The resistant state did not require the continued presence of virus.

Animals↗
PubMed1984

Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence.

We studied the mechanism of lymphocytic choriomeningitis virus (LCMV) persistence and the suppression of cytotoxic T lymphocyte (CTL) responses in BALB/c WEHI mice infected at birth with LCMV Armstrong strain. Using adoptive transfer experiments we found that spleen cells from persistently infected (carrier) mice actively suppressed the expected LCMV-specific CTL response of spleen cells from normal adult mice. The suppression was specific for the CTL response and LCMV -specific antibody responses were not affected. Associated with the specific CTL suppression was the establishment of persistent LCMV infection. The transfer of spleen or lymph node cells containing LCMV -specific CTL resulted in virus clearance and prevented establishment of the carrier state. The suppression of LCMV -specific CTL responses by carrier spleen cells is not mediated by a suppressor cell, but is due to the presence of genetic variants of LCMV in spleens of carrier mice. Such virus variants selectively suppress LCMV-specific CTL responses and cause persistent infections in immunocompetent mice. In striking contrast, wild-type LCMV Armstrong, from which these variants were generated, induces a potent CTL response in immunocompetent mice and the LCMV infection is rapidly cleared. Our results show that LCMV variants that emerge during infection in vivo play a crucial role in the suppression of virus-specific CTL responses and in the maintenance of virus persistence.

Acute Disease↗
PubMed2005

Treatment of persistent infection after anterior cruciate ligament surgery.

Infection after anterior cruciate ligament reconstruction that persists despite debridement is a challenging problem with limited information available in the literature. Our purpose was to determine whether an aggressive protocol would be effective in treating these persistent infections. This is a retrospective review of five consecutive patients with persistent septic arthritis of the knee after anterior cruciate ligament reconstruction. All patients previously had one to three irrigation and debridement procedures that failed to control the infection. Our treatment protocol consists of arthrotomy, complete synovectomy, removal of any implants, graft removal, and curettage of the femoral and tibial tunnels. Cultures are obtained from many sources (joint fluid, synovial lining, graft, and bone) and antibiotic therapy is given for 6 weeks. At a median followup time of 20 months (range, 6-27 months) infection was controlled in all patients. Three of five infections (60%) were polymicrobial. In these cases, different organisms were cultured from multiple tissue samples. Tunnel osteomyelitis was present in three of five patients (60%). Persistent septic arthritis of the knee after anterior cruciate ligament reconstruction can be controlled with a protocol based on radical debridement. Polymicrobial infections may be present and multiple cultures from different sources are required to identify all pathogens.

Adult↗
PubMed2003

Human polyomavirus BK (BKV) transiently transforms and persistently infects cultured osteosarcoma cells.

Human polyomavirus BK (BKV) DNA and proteins have been detected in a number of bone tumours. We therefore investigated whether BKV infection might initiate transformation of human anchorage-dependent osteosarcoma cells in vitro. Infection of the osteosarcoma cell line U-2OS with a naturally occurring BKV strain resulted in soft agarose competent cell clones. In a subclone, designated U-2OS15E, approximately 10-20% of the cells contained episomal BKV genomes. A corresponding proportion of cells expressed BKV proteins and produced viral progeny. This proportion was not increased by BKV superinfection. Furthermore, U-2OS15E cells were resistant to SV40 infection. The transformed status of U-2OS15E cells lasted only for a few passages. However, the persistently infected cells produced infectious virions for more than 300 generations. In addition to representing a model system for persistent BKV infection, the uninfected and persistently BKV-infected cell cultures are useful tools for control and calibration of in situ BKV nucleic acid and protein detection methods.

Animals↗
PubMed1979

Mechanism of rejection of virus persistently infected tumor cells by athymic nude mice.

Cell lines known to be tumorigenic in the nude mouse were modified by rendering them persistently infected (P.I.) with a variety of RNA viruses, including measles, mumps, vesicular stomatitis virus, and influenza. Although as few as 100 HeLa or BHK cells produced tumors in 100% of nude mice, as many as 2 x 10(7) of the same cells P.I. with viruses failed to produce tumors. An active host response responsible for restricting the growth of the P.I. cells was suggested by the findings of marked mononuclear cell infiltrates at the inoculation sites and the inability of irradiated nude mice to reject them. An analysis of the in vitro cytotoxic activity of spleen cells from normal nude mice indicated that: (a) P.I. cell lines, but not uninfected cell lines, were susceptible to spontaneous cytotoxicity; (b) in vivo inoculation of P.I. lines induced an enhanced cytotoxic activity for P.I. targets in vitro, and this induction was not specific either for inducing virus or cell line; and (c) the effector cell had the characteristics for natural killer (NK) cells. Although the specificity of recognition of the various P.I. cell lines remains unclear, cold competition experiments indicated that blocking the killing of one P.I. cell line, e.g. HeLa-measles, could be achieved only by unlabeled homologous cells, i.e. HeLa-measles, and not by uninfected cells or other P.I. lines. A variant subline of BHK cells P.I. with VSV was selected for its ability to withstand the rejection process in nude mice. These cells formed metastatic and invasive tumors in nude mice. Although they were the most potent inducers in vivo of NK cell activity against various P.I. targets, they were the most resistant of the P.I. lines to NK cell cytotoxicity in vitro. In this system there was a good correlation between tumor rejection in vivo and susceptibility to NK cells in vitro. The present results suggest that NK cells may play a significant role in both rejection of tumor cells, and in resistance to viruses, particularly persistent infections.

Animals↗
PubMed1998

Human polyomavirus JC control region variants in persistently infected CNS and kidney tissue.

The question of a possible role for JC virus (JCV) genomic rearrangements in the pathogenesis of progressive multifocal leukoencephalopathy (PML) was addressed by analysis of the genomic complexity and the transcriptional control region (TCR) of the JCV DNA population in persistently infected CNS and kidney tissue. After cloning of full-length viral DNA, no extensive changes were detected in the coding regions of the JCV genome by restriction analysis suggesting an intact JCV DNA population. For further analysis of the distribution of JCV subtypes, the non-coding region was amplified by PCR. Molecular analysis revealed homogeneous JCV TCR populations in almost 50% of the individuals. Heterogeneity was found in two CNS samples with three and five different JCV subtypes, respectively, and in four kidney specimens with two TCR subtypes. Altogether, seven TCR subtypes were identified. One in each group represented single promoter element TCRs without duplication of sequences. The TCR of the major variant JCV-W1 was comparable in sequence and structure to that of the PML prototype JCV Mad-1 DNA. The identification of dominant PML-derived JCV TCR subtypes in most persistently infected individuals suggests that rearrangements of the JCV TCR can be associated with the persistent state of infection. However, it appears unlikely that PML-associated JCV subtypes are generated anew in each individual host in the course of persistence. The findings rather suggest that a limited number of stable JCV subtypes circulate in different geographical regions of the world.

Adult↗
PubMed1995

Antibodies to the nonstructural protein of parvovirus B19 in persistently infected patients: implications for pathogenesis.

Three patients with persistent parvovirus B19 infection, as documented by the prolonged presence of IgM directed to the viral capsid proteins and detection of viral DNA in serum by dot-blot hybridization or polymerase chain reaction (PCR), were investigated for the presence of antibodies to the nonstructural protein NS-1 of parvovirus B19. This was done by using an ELISA based on recombinant NS-1 protein. Whereas control sera displayed no reactivity, sera from persistently infected patients showed a strong specific antibody response to NS-1. Patients were followed for 3-18 months, during which IgM titers declined but IgG directed to the nonstructural protein remained detectable. The appearance of NS-1-specific antibodies might indicate an altered course of viral infection leading to the establishment of persistently active infection and subsequent destruction of cells of nonerythroid lineage.

Adult↗
PubMed2002

Matrix protein mutations contribute to inefficient induction of apoptosis leading to persistent infection of human neural cells by vesicular stomatitis virus.

In a model system to study factors involved in the establishment of a persistent viral infection that may lead to neurodegenerative diseases, Indiana and New Jersey variants of vesicular stomatitis virus (VSV) with different capacities to infect and persist in human neural cells were studied. Indiana matrix (M) protein mutants and the wild-type New Jersey strain persisted in the human neural cell line H4 for at least 120 days. The Indiana wild-type virus (HR) and a non-M mutant (TP6), both unable to persist, induced apoptosis more strongly than all the other variants tested, as indicated by higher levels of DNA fragmentation and caspase-3-like activity. Transfection of H4 cells with mRNA coding for the VSV M protein confirmed the importance of this protein in the induction of apoptosis. Furthermore, the pan-caspase inhibitor ZVAD-fmk maintained cell survival to about 80%, whereas inhibition of caspase-8, caspase-9, or both only partially protected the cells against death, consistent with the fact that anti-apoptotic molecules from the Bcl-2 family also protect cells from death only partially. These results suggest that VSV activates many pathways of cell death and that an inefficient induction of caspase-3-related apoptosis participates in the establishment of a persistent infection of human neural cells by less virulent VSV variants.

Amino Acid Chloromethyl Ketones↗
PubMed1982

Restricted viral RNA synthesis in establishment of persistent infection in Vero cells with a Sendai virus mutant.

It was previously shown that a temperature-sensitive mutant of Sendai virus, ts-23, readily establishes persistent infection in Vero cells at 37 C, a permissive temperature for growth of the mutant. In the present study, it was demonstrated that the virus yield from ts-23-infected Vero cells at 37 C began to decrease 48 to 72 hr postinfection, after an initial phase of high virus production. Before the decrease in virus production, the formation of viral nucleoprotein declined, although synthesis of all species of viral protein continued. It was suggested that the limited formation of viral nucleoprotein and the decrease in virus production were due to the restriction of viral RNA synthesis which began to occur early after infection in ts-23-infected cells at 37 C. The mutant has a temperature-sensitive defect in RNA polymerase activity and the temperature 37 C, used for establishment of persistent infection, would be a semi-permissive temperature for the RNA polymerase activity of the mutant. The ts-23 mutant interfered with the replication of the parental wild virus in Vero cells at 37 C.

Animals↗