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PubMed1985

Establishment and characterization of a persistent infection of MDBK cells with herpes simplex virus.

A persistent, dynamic-state infection of a variant of herpes simplex virus type 1 strain MP [HSV-1 (MP)] in MDBK cells was established without supportive measures and maintained for over three years by routine passaging of the cells at 7-9 day intervals. The infection was characterized by a cyclic pattern of monolayer damage and reconstitution, correlated with virus production, which was most evident when the interval between subcultures was intentionally prolonged and the cells were left undisturbed. Occasional periods of cell crisis, with increased virus replication and extensive cytopathology, occurred. Passaging of the cells at higher density avoided eventual loss of the culture during the most severe crises. Presence of specific antibodies did not alter the course of infection. Interferon was constantly found during periods of cell crisis; it appeared on the second day after subculture, reached a maximum in correspondance of the first peak of cytopathology, and disappeared well before the onset of the second wave of cytopathology. Addition of exogenous interferon cured the cells of infection. Defective interfering particles could not be found. Virus isolated during persistence differed from parental virus regarding plaque morphology, temperature sensitivity of growth, and electrophoretic pattern of infected cells glycoproteins. A discussion on the possible mechanisms of persistence is provided.

Animals↗
PubMed1996

Spontaneous, persistent infection of a B-cell lymphoma with adenovirus.

An adenovirus culture-positive lymphoblastoid cell line was derived from a bone marrow transplant recipient with fatal B-cell lymphoproliferative disease and adenovirus pneumonia. At autopsy, focal areas of the lymphoma infiltrating the patient's lung were positive for adenovirus proteins by immunohistochemical staining. The Epstein-Barr virus-transformed B-cell line Mk, established from pleural fluid cells, contained adenovirus virions in both the nucleus and the cytoplasm by electron microscopy. The majority of Mk cells expressed adenovirus proteins and produced a high level of infectious adenovirus by plaque assay analysis. However, in contrast to the rapid cell death induced by adenovirus in other permissive cell lines, Mk was maintained stably in tissue culture for 6 months. These data indicate that adenoviral replication is not sufficient for cell lysis and confirm that adenovirus can cause persistent infection in human lymphoid cells in vivo.

Adenoviridae Infections↗
PubMed2006

Persistent infection with and serologic cross-reactivity of three novel murine noroviruses.

According to serologic testing, murine norovirus is the most prevalent viral pathogen in contemporary laboratory mice. Previously, murine norovirus 1 (MNV-1) was the only norovirus reported to infect research mice. In this study, 3 novel murine norovirus strains--MNV-2, MNV-3, and MNV-4--were isolated from geographically separate mouse research colonies. All 4 murine norovirus strains used as individual antigens in microsphere fluorescent immunoassays displayed serologic cross-reactivity to serum from mice inoculated with MNV-1, MNV-2, MNV-3, or MNV-4. In addition, reverse transcriptase-polymerase chain reaction analysis at 8 wk postinoculation detected virus in the feces and tissues of all mice experimentally inoculated with MNV-2, MNV-3, or MNV-4. This finding suggests that mice can have prolonged fecal shedding of and can become persistently infected with murine noroviruses.

Animals↗
PubMedDate not supplied

[Is sarcoidosis a chronic persistent infection?].

The study carried out with the use of microbiological diagnostic methods has revealed that in 67% of cases specimens obtained from sarcoidosis patients for analysis contain different forms of mycobacteria (typical Mycobacterium tuberculosis and granular forms of mycobacteria). The content of typical and granular forms of mycobacteria detected in diagnostic specimens has been shown to differ, depending on the clinical form of sarcoidosis: as a rule, in cases of the sluggish course of sarcoidosis granular forms of mycobacteria are detected, while during the exacerbation of the disease and in cases of the acute course of newly diagnosed sarcoidosis the proportion of typical M.tuberculosis increases. To verify M.tuberculosis with greater certainty, two highly sensitive and specific amplification test systems have been developed on the basis of polymerase chain reaction. In this article the goals of microbiological and molecular genetic investigations which may jointly give direct proofs of the etiological importance of mycobacteria in sarcoidosis are considered and discussed; sarcoidosis may probably be regarded as chronic persistence infection.

Animals↗
PubMed2000

Salmonella typhimurium proliferates and establishes a persistent infection in the intestine of Caenorhabditis elegans.

Genetic analysis of host-pathogen interactions has been hampered by the lack of genetically tractable models of such interactions. We showed previously that the human opportunistic pathogen Pseudomonas aeruginosa kills Caenorhabditis elegans, that P. aeruginosa and C. elegans genes can be identified that affect this killing, and that most of these P. aeruginosa genes are also important for mammalian pathogenesis. Here, we show that Salmonella typhimurium as well as other Salmonella enterica serovars including S. enteritidis and S. dublin can also kill C. elegans. When C. elegans is placed on a lawn of S. typhimurium, the bacteria accumulate in the lumen of the worm intestine and the nematodes die over the course of several days. This killing requires contact with live bacterial cells. The worms die with similar kinetics when placed on a lawn of S. typhimurium for a relatively short time (3-5 hours) before transfer to a lawn of E. coli. After the transfer to E. coli, a high titer of S. typhimurium persists in the C. elegans intestinal lumen for the rest of the worms' life. Furthermore, feeding for 5 hours on a 1:1000 mixture of S. typhimurium and E. coli followed by transfer to 100% E. coli, also led to death after several days. This killing correlated with an increase in the titer of S. typhimurium in the C. elegans lumen, which reached 10,000 bacteria per worm. These data indicate that, in contrast to P. aeruginosa, a small inoculum of S. typhimurium can proliferate in the C. elegans intestine and establish a persistent infection. S. typhimurium mutated in the PhoP/PhoQ signal transduction system caused significantly less killing of C. elegans.

Animals↗
PubMed1984

The immune response of the mouse to lymphocytic choriomeningitis virus. IV. Enumeration of antibody-producing cells in spleens during acute and persistent infection.

The solid-phase immunoenzymatic technique for the enumeration of single rat cells producing antibodies against ovalbumin has been adapted to mouse cells producing antibodies against lymphocytic choriomeningitis (LCM) virus. After intravenous (i.v.) infection with 10(3) infectious units, IgM- and IgG-producing cells appeared on days 4 and 5, respectively. They rose to high numbers on days 7, 8, and 9 and were still detectable on day 38. After a second i.v. inoculation of 10(7) infectious units, antibody-producing cells (APC), most of which made IgG, appeared faster and reached much higher numbers. Mutatis mutandis, very similar results were obtained with mice inoculated with vesicular stomatitis virus. Antibodies were specific as to virus, but probably corresponded to more than one viral antigen. Relatively low numbers of APC were also detected in the spleens of NMRI strain carrier mice, which develop severe immune complex disease in later life, but not in spleens of persistently infected young mice of strains that remain free of late immune complex disease, namely CBA/J, C3H/HeJ, and gray house mice; APC were detected in spleens of aging CBA/J but not gray house mice.

Acute Disease↗
PubMed1986

Homology between HBV-DNA and a sequence regulating the interferon-induced antiviral system: possible mechanism of persistent infection.

Treatment of hepatitis B virus (HBV)-infected hepatocytes with lymphoblastoid alpha-interferon (IFN) leads to an increased expression of the core antigen (HBcAg) and reduced expression of surface antigen (HBsAg). We have identified the presence of a nucleotide sequence at the start of the HBc gene in the hepatitis B virus genome similar to a consensus sequence known to occur upstream from genes induced by IFN in mammalian cells. It is possible that interferon influences the expression of the viral genes because of the presence of this homologous sequence. This sequence in the viral genome may determine the site of integration of the virus and could influence the ability of the cell containing the integrated viral sequence to respond to interferon. This "neutralisation" of the interferon system by viral integration might not only facilitate persistent infection but might also adversely affect response to alpha-interferon therapy.

Biopsy↗
PubMed1993

Leader-mRNA junction sequences are unique for each subgenomic mRNA species in the bovine coronavirus and remain so throughout persistent infection.

The common leader sequence on bovine coronavirus subgenomic mRNAs and genome was determined. To examine leader-mRNA junction sequences on subgenomic mRNAs, specific oligodeoxynucleotide sets were used in a polymerase chain reaction to amplify junction sequences from either the positive-strand mRNA (eight of nine total identified species) or the negative-strand anti-mRNA (six of the nine species), and sequenced. The mRNA species studied were those for the N, M, S, and HE structural proteins and the 9.5-, 12.7-, 4.8-, and 4.9-kDa putative nonstructural proteins. By defining the leader-mRNA junction sequence as the sequence between (i) the point of mismatch between the leader and genome and (ii) the 3' end of the consensus heptameric intergenic sequence [(U/A)C(U/C)AAAC)], or its variant, a unique junction sequence was found for each subgenomic mRNA species studied. In one instance (mRNA for the 12.7-kDa protein) the predicted intergenic sequence UCCAAAC was not part of the junction region, and in its place was the nonconforming sequence GGTAGAC that occurs just 15 nt downstream in the genome. Leader-mRNA junction sequences found after 296 days of persistent infection were the same as those found during acute infection (< 18 hr postinfection). These data indicate that, in contrast to the closely related mouse hepatitis virus, the bovine coronavirus maintains a stable leader-mRNA junction sequence for each mRNA. Interestingly, this stability may be related to the fact that a UCUAA sequence element, postulated by others to be a regulator of the leader-mRNA fusion event, occurs only once within the 3' flanking sequence of the genomic leader donor and once at intergenic sites in the bovine coronavirus genome, whereas it occurs two to four times at these sites in the mouse hepatitis coronavirus.

Animals↗
PubMed2001

Sequence variations of hepatitis B virus promoter regions in persistently infected patients.

The HBV in the sera of two chronic active hepatitis patients were analyzed for the promoter sequence heterogeneity. In most cases, the proportion of any particular clone in the total viral populations was less than 50%, showing high mutation rates. In contrast, promoter sequences of HBV from asymptomatic carriers revealed only a few point mutations with no deletions. HBV in chronic patient harbored variants with multiple mutations throughout promoters including 1762 (A-to-T), 1764 (G-to-A) double mutation in C promoter and deletions near CCAAT site in S promoter. Unlike other three promoter regions, C, pre-S1 and S, of HBV which revealed a high level of sequence heterogeneity, the X promoter region (from nt985 to 1430) showed little sequence heterogeneity within a patient. However, the predominant viral clones in two patients were quite different from each other. In addition to mutations in promoter regions, a deletion mutation in the translation start codon was also found in pre-S1 gene. The results in this report indicate that the mutation rates are not the same in all four promoters and that one of the strategies for maintaining persistent infection could be through mutations in viral promoters which then impair the balance of viral gene expressions.

Adult↗
PubMed1984

Coestablishment of persistent infection and oncogenic transformation of hamster embryo cells by equine cytomegalovirus.

Semipermissive, primary hamster embryo (HE) cells were morphologically transformed in vitro by infection with UV-irradiated equine cytomegalovirus (equine herpesvirus type 2; ECMV). Cell lines (designated EC-1-3) were established independently from foci and were shown to exhibit growth and biological properties typically associated with transformed cells: altered morphology, loss of contact inhibition, increased saturation density, decreased generation time, immortality in culture, normal growth in low concentrations of serum, colony formation in soft agar, and resistance to ECMV superinfection. All ECMV transformed cells were restrictive for the replication of equine herpesvirus type 1 (EHV-1) which shares 2.9% homology with ECMV and replicated to high titers in normal HE cells. All EC cell lines were oncogenic in immunocompetent syngeneic LSH hamsters. Tumor cell lines were established from selected malignant fibrosarcomas that developed at the site of injection. Two of the transformed cell lines (EC-2 and EC-3) were found to be persistently infected and to release infectious ECMV from 0.5 to 2% (EC-2) and 0.8 to 5% (EC-3) of the total cell populations. The transformed cell line EC-1 as well as all tumor cell lines were virus nonproducers. Data from DNA-DNA reassociation analyses indicated the presence of 8-32 ECMV genome equivalents per productive EC-2 cell and greater than 300 ECMV genome equivalents per productive EC-3 cell. Small amounts of subgenomic ECMV DNA sequences were detected in the nonproducer EC-1 transformed cells and in all tumor cell lines (EC-1T, -2T, -3T). Some of these DNA sequences must be expressed since ECMV-specific polypeptides were demonstrated in all transformed and tumor cell lines by indirect immunofluorescence using antiserum to ECMV-infected cell extracts and since the sera of tumor-bearing hamsters contained ECMV antibody as detected by an ECMV plaque reduction assay.

Animals↗
PubMed2001

Tick-borne encephalitis virus NS1 glycoprotein during acute and persistent infection of cells.

Tick-borne encephalitis virus (TBEV) was propagated in porcine embryo kidney (PS) cells until 48 h whereas human kidney (RH) cells maintained the virus persistence during at least 2 months. One of possible reasons of flavivirus chronic infection might be abnormal NS1 gene expression. Immunoblotting with monoclonal antibodies (MAbs) revealed the similarity of the intracellular and secreted NS1 nonstructural glycoprotein size and linear antigenic determinants in both the infected cell lines. However, according to the competitive binding of MAbs with the TBEV NS1 extracellular glycoprotein, its contiguous epitopes differed for acute or persistent infection. To map the TBEV NS1 glycoprotein antigenic determinants its recombinant analogues were used. All the studied MAbs could bind with the full-length NS1 recombinant protein. Deletion of the TBEV NS1 gene internal region resulted in defective NS1d1 protein without the region between 269 and 333 a.a. Lack of NS1d1 binding with 20B4 MAb and diminished binding with 22H8 and 17C3 MAbs permitted to map their antigenic determinants within or nearby deleted region, respectively. Interaction of other MAbs with the NS1 and NS1d1 recombinant proteins did not differ, suggesting that their epitopes were located in the region of N-terminal 268 a.a. or C-terminal 19 a.a. of the TBEV NS1 protein. The second NS1d2 truncated protein contained the first N-terminal 33 a.a. of the TBEV NS1 protein and was able to bind with 29G9 MAb. Taken together the data stand for the differences in the N-terminal structure of the TBEV NS1 multimers secreted from the acute and persistent infected cells whereas the intracellular and secreted monomer processing was the same. The modified NS1 protein oligomers in the RH cellular line might slow virus replication and could result in the TBEV persistence.

Animals↗
PubMed1995

Lymphocyte-tropic simian immunodeficiency virus causes persistent infection in the brains of rhesus monkeys.

Molecularly cloned SIVmac239 is the prototypical SIVmac lymphocyte-tropic virus that replicates productively in lymphocytes but poorly in macrophages. In macaques, the virus causes activation and productive infection of T lymphocytes which invade the central nervous system (CNS) early after infection in the animal. However, infected animals develop immunosuppression and AIDS but rarely overt neurological disease. In this study, we examined multiple regions of the brain and spinal cord for the presence of SIV env sequences and histological lesions in five macaques that had been infected with SIVmac239 for 1.7 to 2.25 years. Histopathological examination of the brain revealed no lesions consistent with encephalitis; however, viral DNA was found in all five brains. In one animal the virus caused infection in a widely disseminated pattern from the frontal cortex to the distal end of the spinal cord, whereas in the other four animals infection in the CNS occurred in a nonspecific, focal pattern. Sequence analyses were performed on gp120 sequences isolated from selected regions of the CNS and compared to gp120 sequences isolated from corresponding lymph nodes, a tissue known to support productive replication of SIVmac239. Examination of the viral sequences from the CNS tissue from two animals (macaques 10F and 14F) revealed a low mutation rate when compared to the sequences isolated from the lymph node tissues. The percentage change in the amino acid sequence was approximately 1% for CNS clones versus > or = 3% for clones isolated from the lymph node. The majority of the CNS viral sequences of macaques 10F and 14F had none of the genetic markers shown in a previous study to be associated with macrophage-tropic variants and indeed retained a nucleotide sequence of similar to the original lymphocyte-tropic virus used for inoculation despite almost 2 years of persistent infection in the animals. Construction of chimeric viruses with V1-V5 regions of selected macaque 10F and macaque 14F CNS-gp120 clones confirmed the predicted lymphocyte-tropic nature of these env genes. In contrast, the gp120 sequences isolated from the CNS tissue of one of the other three animals (macaque 13F) had a mutation rate comparable to that observed for the lymph node clones. The CNS clones from this animal had amino acid substitutions that were previously shown to be associated with macrophage tropism. Compared to the chimeric viruses constructed with V1-V5 sequences from macaques 10F and 14F, viruses constructed with the V1-V5 sequences of several macaque 13F brain clones did not yield infectious virus.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1994

Repeated and persistent infection with Chlamydia and the development of chronic inflammation and disease.

Chlamydia trachomatis is an important human pathogen that mediates disease processes capable of inflicting permanent damage. Aggressive inflammatory responses to repeated infections, and to a persistent form of this intracellular bacterium, are thought to initiate the pathogenic events that lead to the debilitating sequelae of blinding trachoma and infertility.

Chlamydia Infections↗
PubMed1986

Rapid emergence of novel antigenic and genetic variants of equine infectious anemia virus during persistent infection.

Previous results from our laboratory have demonstrated that equine infectious anemia virus displays structural variations in its surface glycoproteins and RNA genome during passage and chronic infections in experimentally infected Shetland ponies (Montelaro et al., J. Biol. Chem. 259:10539-10544, 1984; Payne et al., J. Gen. Virol. 65:1395-1399, 1984). The present study was undertaken to obtain an antigenic and biochemical characterization of equine infectious anemia virus isolates recovered from an experimentally infected pony during sequential disease episodes, each separated by intervals of only 4 to 8 weeks. The virus isolates could be distinguished antigenically by neutralization assays with serum from the infected pony and by Western blot analysis with a monoclonal antibody against the major surface glycoprotein gp90, thus demonstrating that novel antigenic variants of equine infectious anemia virus predominate during each clinical episode. The respective virion glycoproteins displayed different electrophoretic mobilities on sodium dodecyl sulfate-polyacrylamide gels, indicating structural variation. Tryptic peptide and glycopeptide maps of the viral proteins of each virus isolate revealed biochemical alterations involving amino acid sequence and glycosylation patterns in the virion surface glycoproteins gp90 and gp45. In contrast, no structural variation was observed in the internal viral proteins pp15, p26, and p9 from any of the four virus isolates. Oligonucleotide mapping experiments revealed similar but unique RNase T1-resistant oligonucleotide fingerprints of the RNA genomes of each of the virus isolates. Localization of altered oligonucleotides for one virus isolate placed two of three unique oligonucleotides within the predicted env gene region of the genome, perhaps correlating with the structural variation observed in the envelope glycoproteins. Thus these results support the concept that equine infectious anemia virus is indeed capable of relatively rapid genomic variations during replication, some of which result in altered glycoprotein structures and antigenic variants which are responsible for the unique periodic disease nature observed in persistently infected animals. The findings of envelope specific differences in isolates of visna virus and of human T-cell lymphotropic virus III (acquired immune deficiency syndrome-related virus) suggest that this variation may be a common characteristic of the subfamily Lentivirinae.

Animals↗
PubMed2005

Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection.

After acute infection Epstein-Barr virus (EBV)-specific memory CD8+ T cells exit cell cycle, and a proportion of these antigen-experienced cells re-express CD45RA (CD45 which predominantly express exon A). However, the signals involved are not known. We investigated the roles of interleukin 15 (IL-15) and interferon-alpha/beta (IFN-I) in these processes, since these mediators have a crucial but undefined role in the maintenance of CD8+ T-cell memory. We show that IFN-I (but not IL-15) allows activated EBV-specific CD8+ T cells to leave cell cycle without entering apoptosis. This was associated with up-regulation of the cyclin inhibitor p27, but not of CD45RA. In contrast, IL-15 (but not IFN-I) induced "homeostatic" proliferation and CD45RA re-expression by these cells in vitro. Different signals, therefore, induce quiescence and CD45RA re-expression in activated EBV-specific CD8+ T cells. After T-cell receptor (TCR) activation freshly isolated CD45RA+ antigen-experienced CD8+ T cells show poor proliferative activity but are highly cytotoxic and secrete IFN-gamma efficiently. This suggests functional reprogramming toward effector function but away from proliferation. The induction of quiescence and the generation of proliferation-independent effector CD8+ T cells that re-express CD45RA may minimize the impact of replicative senescence in virus-specific populations that would otherwise occur during decades of persistent infection.

CD8-Positive T-Lymphocytes↗
PubMed1997

Emergence and selection of HBV variants in an anti-HBe positive patient persistently infected with quasi-species.

BACKGROUND/AIMS: Infection with the hepatitis B e antigen (HBeAg) negative variant of hepatitis B virus (HBV) causes chronic liver disease characterised by occasional acute exacerbations. This virus exhibits a high prevalence of mutations in the core region. Our aim was to study the changes in the pre-core/core region of the virus in relation to exacerbations of the disease. METHODS/RESULTS: We performed direct sequencing on DNA amplified from 7 sequential sera taken over a 5-year period from a hepatitis B surface antigen (HBsAg) and anti-HBe positive Greek patient infected with the HBeAg negative variant. The patient had chronic hepatitis with several acute exacerbation episodes and underwent interferon therapy twice. We found significant variability in the core region at different time points. To determine whether these variants were present in the initial serum sample and subsequently selected under immune pressure or whether they arose de novo during the course of the disease, we cloned the pre-core/core region from 4 sera before and after episodes of acute exacerbation. Fifteen clones from each time point were sequenced. Fourteen nucleotide mutations in the pre-core/core region were recorded, 7 (50%) of which led to amino-acid substitutions. All the amino-acid changes occurred at recognised B- and CD4+ epitopes. The cloning results indicate the presence of quasi-species in all the samples investigated. Some of the variants present as a minor population in the first sample appear to have been selected and become dominant in subsequent sera. However, the emergence of novel variants, not present at a detectable level in earlier samples, during the course of the disease, was also established. The quasi-species nature of HBV only became apparent after the cloning experiments and was not obvious from the direct sequencing results. CONCLUSIONS: New dominant variants occurring during the course of the disease arose either by the selection of pre-existing mutants that were not detected by direct sequencing or by mutation of existing strains. All changes were located within B- and CD4+ epitopes. The continuous production and selection of variants may enable virus to evade elimination by the immune system, resulting in persistent infection.

Adult↗
PubMed1996

Bovine herpesvirus type-4 (BHV-4) persistently infects cells of the marginal zone of spleen in cattle.

Bovine Herpes virus type 4 (BHV-4) has the ability to persist during long post-infection periods in spleen and other lymphoreticular tissues of cattle and laboratory rabbits. Our previous studies indicated that splenic macrophages are the main reservoir of this persistent herpesvirus infection in rabbits. Now we report the use of in situ hybridization (ISH) and cell separation methods to characterize the cellular localization of persistent BHV-4 in cattle. Using cloned sub-genomic probes of BHV-4 DNA labelled with 35S, we detected BHV-4 nucleic acids in cells of the marginal zone of spleen from persistently infected cattle and rabbits. In addition, cell separation studies indicated that a non-T, non-B cell population of the bovine spleen harbours BHV-4. This association requires cell integrity and in vitro co-cultivation for re-expression of the persistent virus. We were also able to detect BHV-4 by explantation/co-cultivation from several other tissues of cattle including trigeminal ganglia, urinary bladder, kidney, lung and several lymphoid tissues including lymph nodes and thymus.

Animals↗
PubMed1988

[Neurosyphilis in HIV infection: persistence after high-dose penicillin therapy].

Ten years after treatment of secondary syphilis a 44-year-old otherwise asymptomatic HIV-infected patient developed acute meningovascular syphilis with multifocal manifestations and neurological deficit. Whether it was a reactivation or new infection could not be established. High-dosage intravenous penicillin treatment failed to eliminate completely the CNS disease process. Inflammatory CSF findings with pleocytosis and demonstration of intrathecally formed specific antibodies, still present a year later, made it likely that the syphilitic infection was persisting. The concurrent HIV infection probably aggravated the course of the neurosyphilis. Serological tests for syphilis should be done in every HIV-infected patient, followed by CSF examination if the results are suspicious. Analogous to the known opportunistic CNS infections, a more extensive period of treatment should also be considered in the case of neurosyphilis in HIV-infected patients.

Acquired Immunodeficiency Syndrome↗