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PubMed1997

Role of sialyloligosaccharide binding in Theiler's virus persistence.

Theiler's murine encephalomyelitis viruses (TMEVs) belong to the Picornaviridae family and are divided into two groups, typified by strain GDVII virus and members of the TO (Theiler's original) group. The highly virulent GDVII group causes acute encephalitis in mice, while the TO group is less virulent and causes a chronic demyelinating disease which is associated with viral persistence in mice. This persistent central nervous system infection with demyelination resembles multiple sclerosis (MS) in humans and has thus become an important model for studying MS. It has been shown that some of the determinants associated with viral persistence are located on the capsid proteins of the TO group. Structural comparisons of two persistent strains (BeAn and DA) and a highly virulent strain (GDVII) showed that the most significant structural variations between these two groups of viruses are located on the sites that may influence virus binding to cellular receptors. Most animal viruses attach to specific cellular receptors that, in part, determine host range and tissue tropism. In this study, atomic models of TMEV chimeras were built with the known structures of GDVII, BeAn, and DA viruses. Comparisons among the known GDVII, BeAn, and DA structures as well as the predicted models for the TMEV chimeras suggested that a gap on the capsid surface next to the putative receptor binding site, composed of residues from VP1 and VP2, may be important in determining viral persistence by influencing virus attachment to cellular receptors, such as sialyloligosaccharides. Our results showed that sialyllactose, the first three sugar molecules of common oligosaccharides on the surface of mammalian cells, inhibits virus binding to the host cell and infection with the persistent BeAn virus but not the nonpersistent GDVII and chimera 39 viruses.

Amino Acid Sequence↗
PubMed1997

Oncogenesis of mammary glands, skin, and bones by polyomavirus correlates with viral persistence and prolonged genome replication potential.

A correlation between polyomavirus-induced oncogenesis and viral persistence on the one hand and/or prolonged genome replication potential on the other was established with respect to their respective organ distributions. Prolonged replication potential is defined as the capacity of a genome to replicate in a given organ from the time of infection up to the onset of oncogenesis. This conclusion was derived following intraperitoneal infection of BALB/c mice with wild-type strain A2. Viral genomes were used as parameters of persistence and replication and were detected by Southern blotting and PCR analysis. The major tumor target organs (mammary gland, skin, and bone), which have not been previously analyzed for persistence, were compared with other, non-tumor-prone organs (kidney, liver, lung, spleen, and salivary gland). A progressive loss of viral genomes was observed in all tissues as a function of time postinfection; however, genomes were shown to persist through 20 weeks postinfection in the mammary glands, skin, and bones to an extent similar to that in the previously described kidneys (D. J. McCance, J. Virol. 39:958-962, 1981; W. P. Rowe, J. W. Hartley, J. D. Estes, and R. J. Huebner, Natl. Cancer Inst. Monogr. 4:189-209, 1960). Thus, tumors arise among organs that sustain a persistent infection, but not all such organs develop tumors (e.g., the kidney). The capacity of organs to support de novo replication at various ages, including the age reached when the first tumors are detected, was also determined using a 3-day infection period for ages between 0 and 7 weeks. For all organs tested, a higher level of genomes was observed in organs of mice infected as neonates than in those infected after the age of 3 weeks. However, marked organ-specific differences were seen in the degree and timing of loss of replication. In particular, viral genome replication, although reduced, was maintained in the mammary glands, skin, and bones of adult animals, in contrast to the kidneys. We conclude that organ-specific oncogenesis correlates with two organ-specific parameters: persistence of viral genomes and prolonged viral genome replication potential. This may reflect a requirement for continued viral genome replication and/or gene expression for tumorigenesis. In turn, these parameters may be linked to the tissue-specific continued capacity for cellular division.

Animals↗
PubMed1998

Persistent baculovirus infection results from deletion of the apoptotic suppressor gene p35.

Infection with the wild-type baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) results in complete death of Spodoptera frugiperda (Sf) cells. However, infection of Sf cells with AcMNPV carrying a mutation or deletion of the apoptotic suppressor gene p35 allowed the cloning of surviving Sf cells that harbored persistent viral genomes. Persistent infection established with the virus with p35 mutated or deleted was blocked by stable transfection of p35 in the host genome or by insertion of the inhibitor of apoptosis (iap) gene into the viral genome. These artificially established persistently virus-infected cells became resistant to subsequent viral challenge, and some of the cell lines carried large quantities of viral DNA capable of early gene expression. Continuous release of viral progenies was evident in some of the persistently virus-infected cells, and transfection of p35 further stimulated viral activation of the persistent cells, including the reactivation of viruses in those cell lines without original continuous virus release. These results have demonstrated the successful establishment of persistent baculovirus infections under laboratory conditions and that their establishment may provide a novel continuous, nonlytic baculovirus expression system in the future.

Animals↗
PubMed1998

Critical role for CD4(+) T cells in controlling retrovirus replication and spread in persistently infected mice.

Reactivations of persistent viral infections pose a significant medical problem in immunocompromised cancer, transplant, and AIDS patients, yet little is known about how persistent viral infections are immunologically controlled. Here we describe a mouse model for investigating the role of the immune response in controlling a persistent retroviral infection. We demonstrate that, following recovery from acute Friend virus infection, a small number of B cells evade immunological destruction and harbor persistent virus. In vivo depletions of T-cell subsets in persistently infected mice revealed a critical role for CD4(+) T cells in controlling virus replication, spread to the erythroid lineage, and induction of erythroleukemia. The CD4(+) T-cell effect was independent of CD8(+) T cells and in some cases was also independent of virus-neutralizing antibody responses. Thus, the CD4(+) T cells may have had a direct antiviral effect. These results may have relevance for human immunodeficiency virus (HIV) infections where loss of CD4(+) T cells is associated with an increase in HIV replication, reactivation of persistent viruses, and a high incidence of virus-associated cancers.

Animals↗
PubMed2000

Sialylation of the host receptor may modulate entry of demyelinating persistent Theiler's virus.

Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus of the Cardiovirus genus. Certain strains of TMEV may cause a chronic demyelinating disease, which is very similar to multiple sclerosis in humans, associated with a persistent viral infection in the mouse central nervous system (CNS). Other strains of TMEV only cause an acute infection without persistence in the CNS. It has been shown that sialic acid is a receptor moiety only for the persistent TMEV strains and not for the nonpersistent strains. We report the effect of sialylation on cell surface on entry and the complex structure of DA virus, a persistent TMEV, and the receptor moiety mimic, sialyllactose, refined to a resolution of 3.0 A. The ligand binds to a pocket on the viral surface, composed mainly of the amino acid residues from capsid protein VP2 puff B, in the vicinity of the VP1 loop and VP3 C terminus. The interaction of the receptor moiety with the persistent DA strain provides new understanding for the demyelinating persistent infection in the mouse CNS by TMEV.

Animals↗
PubMed2001

High numbers of viral RNA copies in the central nervous system of mice during persistent infection with Theiler's virus.

The low-neurovirulence Theiler's murine encephalomyelitis viruses (TMEV), such as BeAn virus, cause a persistent infection of the central nervous system (CNS) in susceptible mouse strains that results in inflammatory demyelination. The ability of TMEV to persist in the mouse CNS has traditionally been demonstrated by recovering infectious virus from the spinal cord. Results of infectivity assays led to the notion that TMEV persists at low levels. In the present study, we analyzed the copy number of TMEV genomes, plus- to minus-strand ratios, and full-length species in the spinal cords of infected mice and infected tissue culture cells by using Northern hybridization. Considering the low levels of infectious virus in the spinal cord, a surprisingly large number of viral genomes (mean of 3.0 x 10(9)) was detected in persistently infected mice. In the transition from the acute (approximately postinfection [p.i.] day 7) to the persistent (beginning on p.i. day 28) phase of infection, viral RNA copy numbers steadily increased, indicating that TMEV persistence involves active viral RNA replication. Further, BeAn viral genomes were full-length in size; i.e., no subgenomic species were detected and the ratio of BeAn virus plus- to minus-strand RNA indicated that viral RNA replication is unperturbed in the mouse spinal cord. Analysis of cultured macrophages and oligodendrocytes suggests that either of these cell types can potentially synthesize high numbers of viral RNA copies if infected in the spinal cord and therefore account for the heavy viral load. A scheme is presented for the direct isolation of both cell types directly from infected spinal cords for further viral analyses.

Animals↗
PubMed1989

Endogenous formation of prostanoids in neonates with persistent pulmonary hypertension.

Endogenous formation of thromboxane A2 and prostacyclin were evaluated in seven neonatates with persistent pulmonary hypertension by serial gas chromatographic mass spectrometric determination of their urinary metabolites dinor-thromboxane B2 and dinor-6-keto-prostaglandin F1 alpha, respectively. The patients were studied until their hypertension had resolved on clinical criteria. Urinary excretion of dinor-thromboxane B2 and dinor-6-keto-prostaglandin F1 alpha was increased when the persistent pulmonary hypertension was associated with group B streptococcal (n = 2) and pneumococcal (n = 1) sepsis. Based on urinary metabolite excretion, endogenous formation of thromboxane A2 and prostacyclin did not consistently differ from normal neonates in four patients with non-septic persistent pulmonary hypertension (hyaline membrane disease (n = 2), asphyxia, and meconium aspiration). These data suggest that thromboxane A2 is not a universal mediator of persistent pulmonary hypertension. It may, however, have a role in the pathophysiology of early onset group B streptococcal disease, and persistent pulmonary hypertension of other infectious aetiology. If these findings are confirmed by further studies, thromboxane synthetase inhibition or receptor antagonism may offer a potential therapeutic approach in neonates with persistent pulmonary hypertension associated with sepsis.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

Associations of health related behaviour, social relationships, and health status with persistent physical activity and inactivity: a study of Finnish adolescent twins.

OBJECTIVE: To examine the association between leisure time physical activity over a three year period and health related behaviour, social relationships, and health status in late adolescence as part of a nationwide longitudinal study. METHODS: Five birth cohorts of adolescent twins aged 16 at baseline (n = 5028; 2311 boys and 2717 girls) participated in the study. Questionnaires on leisure time physical activity, other health related behaviour, social relationships, and health status were sent to the twins on their 16th and 17th birthdays and six months after their 18th birthday. The combined response rate to the three questionnaires was 75.8% for boys and 81.7% for girls. Those who answered in all three questionnaires that their frequency of physical activity was 4-5 times a week or more were defined as persistent exercisers, and those who exercised at most twice a month in all three were defined as persistently inactive. Logistic regression analyses were used to identify baseline variables associated with outcome measures. RESULTS: Overall, 20.4% of boys and 13.0% of girls were persistent exercisers and 6.5% of boys and 5.3% of girls were persistently inactive. In both sexes, smoking, irregular breakfast eating, attending vocational school, and poor self perceived current health were significantly associated with persistent inactivity. CONCLUSIONS: Persistent physical inactivity in adolescents is associated with a less healthy lifestyle, worse educational progression, and poor self perceived health. Tailoring methods to promote physical activity may prove useful for influencing other health habits. Such programmes are indicated for vocational schools in particular.

Adolescent↗
PubMed1988

Risk factors for persistent diarrhoea.

With a systematically sampled population of children aged under 5 attending this centre for diarrhoeal disease research during 1983-5 a retrospective analysis of persistent diarrhoea (defined as greater than 14 days' duration) was performed to identify the possible risk factors for this syndrome. Of the 4155 children included in the analysis, 410 (10%) gave a history of persistent diarrhoea. A comparison with children with acute diarrhoea matched for age showed that 11 factors were correlated with persistent diarrhoea, and strongly associated factors were stools with blood or mucus, or both, lower respiratory tract infection, malnutrition, vitamin A deficiency, and antibiotic use before presentation. The peak age was 2 years, and there was no sex difference. Deaths occurred more often in the group with persistent diarrhoea. Although Shigella spp, Campylobacter jejuni, and Giardia lamblia were frequently identified, their rates of isolation were not significantly higher among patients with persistent diarrhoea. No seasonal variation was observed in the rates of persistent diarrhoea. Although the introduction of family food to the diet was associated with higher rates, this factor was difficult to separate from the age dependent risks.

Acute Disease↗
PubMed1991

Prospective hospital based study on persistent diarrhoea.

A total of 383 children aged less than 5 years suffering from acute watery diarrhoea or dysentery were studied in hospital to determine the rate of persistent diarrhoea. Altogether 335 (87.5%) recovered within 13 days. Only in 48 (12.5%) did the diarrhoea continue for 14 days or more, and they were considered as having persistent diarrhoea. Children aged between 7 and 18 months had a significantly increased incidence of persistent diarrhoea. Children suffering from grade II-IV malnutrition constituted the majority (70.8%) of those with persistent diarrhoea. Higher rates of isolation of Shigella flexneri, Shigella dysenteriae 1, and Salmonella typhimurium were observed among patients with persistent diarrhoea than in those with diarrhoea of shorter duration. No positive correlations were observed between the clinical severity of disease at hospital admission and measles. Breast fed babies were not prone to persistent diarrhoea.

Acute Disease↗
PubMed1978

General features of persistent virus infections.

Persistent virus infections are discussed from the virus point of view in terms of the bodily sites in which the infection persists. Glands and body surfaces are thought to be significant because they give the virus protection at the topographical level from immune forces, and because they are appropriate sites for the shedding of virus to the exterior. Germ cells are relevant sites because infection can thus be transmitted vertically from generation to generation in the host. The central nervous system, however, is generally a 'dead end' from which there is no shedding to the exterior. Persistance in blood may be relevant when continued arthropod transmission becomes possible. Most persistent viruses infect lymphoreticular tissues, and this is interpreted by suggesting that it results in an impaired immune response to the infecting virus, which in turn favours persistence. It is suggested that the biological function of virus transformation and the integration of viral into host cell DNA is that it enables the infection to persist in the host and undergo reactivation. Papovaviruses, adenoviruses and oncornaviruses are considered from this point of view.

Adenoviridae Infections↗
PubMed1982

Detection of transient and persistent feline leukaemia virus infections.

A study was made of cats persistently or transiently viraemic with feline leukaemia virus (FeLV) following experimental oronasal infection. Cats of two ages were exposed to the virus. One group was infected when eight weeks old in the expectation that most of the cats would become persistently viraemic, and the second group when 16 weeks old, so that some would show signs of a transient infection and then recover. The periods following infection when virus was detectable in the blood and in the oropharynx were determined for each group. Three methods for detecting viraemia were compared: virus isolation, immunofluorescence on blood smears and an enzyme-linked immunosorbent assay (ELISA). There was good overall agreement among the three tests in detecting virus-positive cats. Virus was found sooner after infection by virus isolation than by the other methods, and virus appeared in the blood slightly sooner in cats which developed persistent viraemia than in transiently viraemic cats. Infectious FeLV was isolated from the oropharynx of all of the persistently viraemic cats, in most cases simultaneously with virus in the plasma. Virus was also isolated from the mouth of most transiently viraemic cats. Under field conditions such transient excretion of virus lasting only a few days would rarely be detected in a single sampling. This might explain how FeLV is maintained in free range urban cats in the absence of a large number of cats with persistent active FeLV infection. For routine diagnosis, immunofluorescence would appear to offer the best chance of differentiating transient and persistent infections by FeLV.

Age Factors↗
PubMed1998

Persistence of the efficacy of doramectin against Ostertagia ostertagi and Cooperia oncophora in cattle.

The persistence of the efficacy of doramectin injectable against Ostertagia ostertagi and Cooperia oncophora was evaluated in two studies in calves. In both, the calves were allocated to six groups of six. Calves in the first control group (C1) and first treated group (T1) received a daily infection of 200 L3 of O ostertagi and 200 L3 of C oncophora; the calves in groups C2 and T2 received a daily infection of 1000 L3 of each species, and groups C3 and T3 received 10,000 L3 of each species per day. The calves in the three treated groups each received 0.2 mg/kg doramectin injectable on day 0. In the first study, the calves were infected for 21 days with Cooperia and for 28 days with Ostertagia, and they were slaughtered on day 33. In the second study, the calves were infected for 21 days with both species, the infections with Cooperia and Ostertagia starting from eight and 15 days, respectively, after the treatment, and the animals were slaughtered on day 40. The calculation of the persistence of the activity of doramectin was based on its efficacy against the different developmental and adult stages of the two parasites. The data from both studies indicated that the efficacy of doramectin against Ostertagia persisted for at least five weeks, but no conclusions could be drawn about the effect of the size of the infective doses on the persistence of the activity. In contrast, the Cooperia worm counts from the second study suggested that the efficacy of doramectin against Cooperia persisted for at least four weeks when the calves were exposed to a low or moderate infection level, whereas at the highest infection level it persisted for between three and four weeks.

Animals↗
PubMed1981

Mechanisms of persistence in arenavirus infections: a brief review.

A characteristic of the arenaviruses is persistent infections in their natural host. Age at infection is an important factor in the establishment of persistence. Infections early in life regularly result in persistence and this appears to be related to the immaturity of the immune system. Persistently infected animals make antibodies to the viral antigens, which indicates that the animals are not tolerant with respect to B cell functions. However, cytotoxic T cells cannot be demonstrated in persistently infected animals, suggesting a defect in effector T cell functions. The mechanisms leading to this defect in cytotoxic T cells have not been resolved. Persistence of arenaviruses in cell cultures is also regularly observed but the molecular basis for survival of the virus and cell in long-term cultures has yet to be clarified.

Animals↗
PubMed1992

Relative persistence capacity of BCG substrains in mouse spleen. Computerized statistical analysis. Multiple comparison.

The relative persistence capacity in mouse spleen of 10 and 9 BCG substrains from liquid and dried vaccines, respectively, was evaluated in two studies. Recoverable BCG colony counts from mouse spleen were determined at given days on solid medium in the two studies during a period of 1-360 and 1-345 days, respectively, after the intravenous BCG vaccination, performed with two different viable units. From 36,000 (study 1) and 21,600 (study 2) recoverable BCG colony counts, 180 and 108 mean relative persistence capacity values were estimated to test the residual virulence during the follow-up time, using computerized statistical analysis. The early and late trends of mean relative persistence capacity of the BCG substrains in mouse spleen were tested by linear regression analysis and analysis of variance and covariance; then with ranked adjusted group mean relative persistence capacity, Gabriel's simultaneous test procedure was performed for multiple comparison to diminish type 1 error in statistical inference and in objective interpretation of the experimental results. The associations of the ranked mean relative persistence capacity of the BCG substrains at the different sacrifice days of mice were also analyzed by Kendall's test of concordance. The early, late, and overall relative persistence capacity reflects the residual virulence of the BCG substrains and provides information on the required protective efficacy (immunogenicity) and adverse reactions (reactogenicity), allowing the appropriate vaccination dose, expressed in viable units of the substrain used, to be determined.

Animals↗
PubMed2003

Persistent LIP activity in memory antisaccades: working memory for a sensorimotor transformation.

The lateral intraparietal area (LIP) contains neurons that are active during the memory interval of memory saccades. We call these "persistent neurons." Here we study the activity of the persistent neurons in memory antisaccades, "motor" (the saccade is made toward the response field, although the response field is not stimulated visually) and "visual" (the response field is stimulated visually, but the movement is away from the field). Most persistent neurons are active during parts of the memory intervals of both visual and motor memory-antisaccades. Typically, these parts significantly overlap each other and together span the entire memory interval. The amplitude of the activity changes systematically during the memory intervals of visual and motor memory antisaccades. These changes are reflected in an antisaccade differential activity, which turns first to the visual direction and then crosses over to the motor direction. Some persistent neurons appear to show the paradoxical activity previously characterized in visual neurons; paradoxical activity accelerates the transition of the neuron's activity from visual to motor. These observations suggest that the persistent neurons reflect working memory for the computation of the antisaccade sensorimotor transformation. Ensembles of persistent neurons with different response fields may make up modules of working memory.

Animals↗
PubMed1990

IgA antigliadin antibodies and persistence of jejunal lesions in adult coeliac disease.

In 46 adult patients with coeliac disease, 41 (89%) of whom were positive for IgA and/or IgG antigliadin antibodies (AGA) when untreated, we investigated after a gluten-free diet the relationship between the persistence of AGA, the persistence of jejunal lesions, and the duration and compliance with the diet. IgG AGA were positive in 21 coeliac patients (46%) after variable periods of gluten-free diet and were associated with IgA positivity only in 4 cases (9%). Both IgA and IgG AGA positivity appeared to be more related to the lack of improvement of the jejunal lesions than to the strictness and duration of gluten withdrawal. Nine coeliacs showed no improvement of jejunal lesions after the gluten-free diet. Of these 9, 4 showed persistent IgA AGA, while the remaining 5 resulted IgAAGA-negative as before when untreated. Though intestinal biopsy remains the best means of determining the positive effect of gluten withdrawal, the persistence of IgA AGA in treated coeliacs is always predictive of the persistence of severe jejunal lesions. The persistence of IgG AGA, on the contrary, should be regarded as an immunological memory.

Adult↗
PubMed2003

Transplantation of enalapril-treated kidneys confers persistent lowering of arterial pressure in SHR.

The kidney plays a critical role in regulating the level of arterial pressure and in the pathogenesis of hypertension. Important evidence has come from studies in which hypertension is generated by transplanting kidneys from genetically hypertensive rats into normotensive recipients, suggesting that the level of blood pressure is strongly influenced by the genetic background of the kidney. We hypothesized that pharmacotherapy could modify specific properties intrinsic to the kidney such that after transplantation, there would be persistent changes in the level of arterial pressure. We determined that angiotensin-converting enzyme inhibitor treatment (enalapril) in spontaneously hypertensive rats induced both a persistent 17% reduction of mean arterial pressure and a persistent change in the kidney. This persistent change in the circulation could be completely transferred to untreated spontaneously hypertensive rats by kidney transplantation; ie, mean arterial pressure in untreated spontaneously hypertensive rat recipients was persistently lowered after transplantation of a kidney from a previously treated spontaneously hypertensive rat donor. In addition, the persistent lowering of mean arterial pressure after enalapril treatment could be completely abolished by implanting an untreated kidney, thereby revealing the importance of the kidney-specific changes. Furthermore, after within-group transplantations, there were no changes in the level of arterial pressure; ie, a 16% difference in mean arterial pressure remained between the 2 groups. The findings revealed that drug-induced changes specific to the kidney determined the level of arterial pressure, thereby suggesting the kidney should be a key therapeutic target for pharmacotherapy.

Angiotensin-Converting Enzyme Inhibitors↗