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Results for “Persistent infection”

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PubMed1978

Initiation and maintenance of persistent infection by respiratory syncytial virus.

Propagation of cells infected with temperature-sensitive (ts) mutants of respiratory syncytial (RS) virus at nonpermissive temperature (39 degrees C) resulted in cytolytic, abortive, or persistent infection, depending on the mutant used to initiate infection. Five mutants from complementation group B produced cytolytic or abortive infections, whereas a single mutant (ts1) from group D and a noncomplbmenting mutant produced persistent infections. The persistently infected culture initiated by mutant ts1 (RS ts1/BS-C-1) has been maintained in serial culture for greater than 100 transfers, and infectious-center assays and immunofluorescent staining indicated that all cells harbored the RS virus genome. RS ts1/BS-C-1 cultures were resistant to superinfection by homologous and some heterologous viruses, and interferon-like activity against some heterologous viruses was present in the culture medium. Small amounts (0.002 to 0.2 PFU/cell) of infectious virus were present in the culture fluid, but autointerfering defective particles were not detected. This released virus formed small plaques and produced persistent infection of BS-C-1 cells at 37 degrees C. The RS ts1/BS-C-1 cells contained abundant RS virus antigen internally, but little at the surface, although the cells showed enhanced agglutinability by concanavalin A. Nucleocapsids and the 41,000-molecular-weight nucleoprotein were present in extracts of both nucleated and enucleated cells. No infectious RS virus was obtained by transfection of DNA from RS tsl/BS-C-1 cells to susceptible BS-C-1 or feline embryo cells under conditions allowing efficient transfection of a foamy virus proviral DNA. It was concluded that persistent infection was maintained in part by a non-ts variant of RS virus partially defective in maturation. The karyotype of the RS ts1/BS-C-1 culture differed from that of unifected cells.

Antigens, Surface↗

PubMed1976

Persistent infection with bovine herpesvirus-1 (infectious bovine rhinotracheitis virus) in cultured hamster cells.

Bovine herpesvirus-1 infection in hamster embryo cells was found to be dependent upon input multiplicity; productive infection was achieved at input multiplicities greater than one, while persistent infection was established when input multiplicities were about 0.5. This persistence was characterized by a noncyclic, minimal degree of cytopathic effect with a low level of released virus. Maintenance of the persistently infected cultures did not require external supportive measures. Subcultivation of the persistently infected cultures led to virus replication followed by CPE and then cell regrowth. With 3 to 4 weeks after subcultivation a persistent infection was re-established. The possible mechanism for the bovine herpesvirus persistence in hamster cells is discussed.

Animals↗

PubMed1978

Isolation of a heterogeneous population of temperature-sensitive mutants of measles virus from persistently infected human lymphoblastoid cell lines.

Two human lymphoblastoid B-cell lines, WI-L2 and 8866, were infected with the Edmonston strain of measles virus at a multiplicity of infection of 10(-6), and stable persistent infections were established. By immunofluorescence and electron microscopy, the vast majority of cells from both cell lines were expressing viral antigens and releasing virion-like particles. However, very little infectious virus could be detected at 37 degrees C, either by an infectious centers assay or by titration of supernates from persistently infected cultures. When cultures were shifted to 31 degrees C, the cells released a population of virus that was temperature-sensitive. Clonal analysis of supernatant virus at 31 degrees C revealed a highly heterogeneous population of temperature-sensitive mutants, differing in plating efficiency ratios, thermolability, and antigen production at the nonpermissive temperature. Factors such as interferon, defective interfering particles, and extracellular virus do not appear to be important in maintaining the persistent carrier state. These studies have important implications for persistent infections of lymphoid cells in vivo, and the slow neurological diseases associated with measles, subacute sclerosing panencephalitis, and multiple sclerosis.

Antibodies, Viral↗

PubMed1977

A persistent infection of baby hamster kidney-21 cells with mumps virus and the role of temperature-sensitive variants.

A persistent infection of baby hamster kidney-21 (BHK-21) cells with mumps virus (BHKpi) was maintained for over 60 cell passages in the absence of antiserum. Viral persistence was demonstrated in the cultures by hemadsorption, immunofluorescence, multinucleate syncytia, and released mumps virus at the level of 10(2)--10(3) fluorescent focus-forming units/ml. No detectable levels of interferon were found in cultures persistently infected with mumps virus. Approximately 85--95% of the cells contained viral antigens. Nuclear fluorescence was observed in the persistently infected cells. Mumps virus from persistently infected clutures (MuVpi) was more heat-labile than wild-type mumps (MuVo) when subjected to 40 degrees C. BHKpi cells had a more rapid doubling time and a higher cloning efficiency in soft agar in comparison to BHK-21 cells. MuVpi was also found to be temperature-sensitive. The temperature-sensitivity of MuVpi was determined by the efficiency of plating at 33 degrees and 39 degrees C. MuVpi readily established a persistent infection in BHK-21 cells with less cytopathology than MuVo, and released temperature-sensitive virus.

Animals↗

PubMed1976

Persistent infection of BHK cells with herpes simplex virus types 1 and 2 in the absence of specific anti-herpetic antibody.

Persistent infection of BHK-21 cells with 5 strains of herpes simplex virus (HSV) type 1 and a 1 strain of HSV type 2 is described. Acute infection only was obtained with two strains of type 1 and one strain of type 2. Persistent infection could not be established in HeLa and rabbit lung cells. Persistent infection of BHK cells proceeded in the absence of specific antibody. Persistently infected cells were more resistant to superinfection with homologous or heterologous HSV as compared to infection of normal BHK cells. No interferon activity was demonstrated in persistently infected cell cultures. The results of virus titration were in accordance with the demonstration of fluorescent antigen of HSV.

Animals↗

PubMed1978

Persistent infection of L cells with vesicular stomatitis virus: evolution of virus populations.

A previous report (Youngner et al., J. Virol. 19:90-101, 1976) documented that noncytocidal persistent infection can be established with wild-type vesicular stomatitis virus (VSV) in mouse L cells at 37 degrees C and that a rapid selection of RNA(-), group I temperature-sensitive (ts) mutants consistently occurs in this system. To assess the selective advantage of the RNA(-)ts phenotype, evolution of the virus population was studied in persistent infections initiated in L cells by use of VSV ts 0 23 and ts 0 45, RNA(+) mutants belonging to complementation groups III and V. In L cells persistently infected with ts 0 23, the ts RNA(+) virus population was replaced gradually by viruses which had a ts RNA(-) phenotype. VSV ts 0 45 (V) has another marker in addition to reduced virus yield at 39.5 degrees C: a defective protein (G) which renders virion infectivity heat labile at 50 degrees C. Persistent infections initiated with this virus (ts, heat labile, RNA(+)) evolved into a virus population which was ts, heat resistant, and RNA(-). These findings suggest that the ts phenotype itself is not sufficient to stabilize the VSV population in persistently infected L cells and also indicate that the ts RNA(-) phenotype may have a unique selective advantage in this system. In addition to the selection of ts RNA(-) mutants, other mechanisms which also might operate in the maintenance of persistent VSV infections of L cells were explored. Whereas defective-interfering particles did not seem to mediate the carrier state, evidence was obtained that interferon may play a role in the regulation of persistent infections of L cells with VSV.

L Cells↗

PubMed1979

Measles virus-specified polypeptide synthesis in two persistently infected HeLa cell lines.

Measles virus-directed protein synthesis was examined in two HeLa cell lines (K11 and K11A) that are persistently infected with wild-type measles virus. Four viral proteins (H, hemagglutination protein; P, nucleocapsid-associated protein; NP, the major nucleocapsid protein; and M, the matrix protein) were readily detected in both cell lines by immune precipitation of [(35)S]methionine-labeled cell extracts followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, three (H, NP, and M) of the four viral proteins in both K11 and K11A cells differed from the corresponding viral proteins synthesized in HeLa cells acutely infected with the parental wild-type virus. In addition, the M protein from K11A cells migrated significantly more slowly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis than the M protein from K11 cells, and there appeared to be slight differences in the H and NP proteins between these two persistently infected cell lines. The altered viral proteins detected in K11 and K11A cells appeared to be the result of viral mutations rather than changes in the host cell, since virus recovered from these cells directed the synthesis of similar aberrant viral proteins in HeLa cells. Virus recovered from K11 cells and virus recovered from K11A cells were both temperature sensitive and grew more slowly than wild-type virus. HeLa cells infected with virus recovered from K11 cells readily became persistently infected, resembling the original persistently infected K11 cells. Thus, viral mutations are associated with persistent measles virus infections in cell cultures.

Capsid↗

PubMed1979

Establishment of persistent infection in BHK-21 cells by temperature-sensitive mutants of Sindbis virus.

Twelve temperature-sensitive (ts) mutants of Sindbis were examined for their ability to establish persistent infection in BHK-21 cells at 39 degrees C. Five of these mutants were able to initiate colony formation in infected cultures, which followed an extensive c.p.e. Two of the mutants were able to establish persistent infections which survived beyond the fifth cell passage p.i. The ability to initiate colony formation was correlated with low reversion of the ts mutation, or with ability to interfer with the multiplication of the wild-type virus. Virus released from persistently infected cultures was not temperature-sensitive. The restriction of virus multiplication in persistently infected cells operated prior to virus-specified RNA synthesis. It is concluded that in this system establishment of persistent infection depends on an inhibition of virus multiplication early in infection and occurs in only a small proportion of infected cells.

Animals↗

PubMed1976

Characterization of measles viruses in establishment of persistent infections in human lymphoid cell line.

Human lymphoid cells (NC-37) were infected with attenuated measles vaccine virus (Schwarz, AIK-C, and CAM-70 strains), subacute sclerosing panencephalitis virus (Mantooth and Halle strains), neurovirulent TYCSA strain, and wild type virus (Edmonston and Toyoshima strains) at an input multiplicity of 0-01. These strains were divided into two groups by their capacity to establish carrier states. CAM-70, Toyoshima, and Edmonston strains did not set up persistent infections in NC-37 cells, whereas AIK-C strain induced chronic cyclic infection and the Schwarz, TYCSA, Mantooth and Halle strains could set up persistent infections and furthermore two types of persistent infections were recognizable. Cells persistently infected with Schwarz strain contained nucleocapsid structures in both nucleus and cytoplasm, and produced infectious virus of 10(4) to 10(5) p.f.u./ml over 100 days after the inoculation of the virus but the cap-formation of measles antigens on the cell membrane was seldom observed. However, in cells persistently infected with TYCSA strain, nucleocapsid structures were rarely observed in the nucleus, but the cap-formation of measles antigens on the cell membrane was often observed. The titre of carried virus was always higher than the number of cells in the range of 10(6) to 10(7) p.f.u./ml. Mantooth strain was similar to Schwarz strain and Halle strain was similar to TYCSA strain in the properties of their carrier states. These carrier states were stable and the cells grew normally for over one year.

Antigens, Viral↗

PubMed1979

Interferon susceptibility of various cell lines persistently infected with haemagglutinating virus of Japan (HVJ).

Various cell lines persistently infected with para-influenza 1 virus, HVJ strain, were less susceptible to the antiviral action of interferon than the same cell lines when not infected with HVJ. When Vero cells persistently infected with a temperature-sensitive strain of HVJ were incubated at 38 degrees C, a non-permissive temperature, they became fully susceptible to interferon, whereas neither the haemadsorbing nor the cell-associated haemagglutinating activity of the virus was expressed. These findings suggest that the lowered interferon susceptibility of virus-carrier cells may be related to the maturation of virus in them. It was found that the low susceptibility of virus-carrier cells to interferon is not due to blocked adsorption of interferon or to inability of the cells to respond tointerferon. Studies with actinomycin D suggest that some step (or steps) before the synthesis of the messenger RNA for the antiviral protein is blocked.

Animals↗

PubMed1978

Establishment and characterization of a subacute sclerosing panencephalitis (measles) virus persistent infection in BGM cells.

Infection of BGM cells with the Halle isolate of subacute sclerosing panencephalitis (SSPE) gave rise to a persistent infection (BGM/Halle), whereas infection of another African green monkey kidney cell line (Vero) under identical conditions led to a lytic infection. The BGM/Halle cells multiplied more slowly than the non-infected cells (even when the medium was changed daily). Under such conditions 10(7) to 10(8) p.f.u./ml/24 h of measles virus was released into the medium. It was established that the persistent infection was not due to the accumulation of thermosensitive mutants and that the virus was not modified as measured by several biological parameters. The virus released from BGM/Halle cells had, however, acquired an ability to give rise to a persistent infection in Vero cells. The quantity of virus released from persistently infected Vero cells was very low (10(2) to 10(3) p.f.u./ml). It was concluded that a host-cell factor plays a role in the restriction of virus replication.

Cell Division↗

PubMed1977

Interferon production and response to exogenous interferon in two cell lines of mouse brain origin persistently infected with Sendai virus.

Two persistently infected cell lines established from C3H mouse brain cells infected in vivo with Sendai virus were shown to differ with respect to interferon (IF) production and response to exogenous IF. MB/Sen carrier cells contained 1-5 per cent antigen positive cells when examined by immunofluorescence, and virus was occasionally recovered from the culture medium. MB/SenAS carrier cells were maintained with 0.16 per cent Sendai antiserum in the supernatant medium. All MB/SenAS cells contained viral antigen and infectious virus was present in the culture medium. MB/Sen released IF spontaneously into the culture medium. Further IF production could be stimulated in MB/Sen by superinfection with Newcastle disease virus (NDV) or vesicular stomatitis virus (VSV). Exogenous IF provided good protection against VSV challenge. In contrast, MB/SenAS produced no IF spontaneously but could be stimulated by NDV and VSV to produce IF. Exogenous IF failed to reduce the amount of VSV released into the supernatant fluid. Replication of VSV was restricted in MB/SenAS as shown by a 2.3 log10 lower virus yield compared to MB/Sen.

Animals↗

PubMed1977

Hamster brain tumor cells persistently infected with measles-subacute sclerosing panencephalitis virus.

A persistent infection was established in a cell line derived from a hamster brain tumor (HBT) with the HBS strain of measles-subacute sclerosing panencephalitis (SSPE) virus. The persistently infected cells (HBT-M) were studied with regard to their growth in vitro and their transplantability in vivo. Although the growth of the HBT-M cells paralleled that of the HBT cells in vitro their transplantability was decreased in weanling hamsters. Hydrocortisone treatment of the hamsters abrogated the lowered transplantability restoring the tumor-producing capacity to levels comparable to the HBT cells. The decreased cell growth of the HBT-M cells in vivo was attributed to the acquisition of measles virus (MV) antigens and the host immune response directed against these new antigens.

Animals↗

PubMed1976

RNA synthesis in BHK 21 cells persistently infected with vesicular stomatitis virus and rabies virus.

Virus-induced RNA synthesis was studied in BHK 21 cells persistently infected with vesicular stomatitis virus (VSV) and rabies virus by labelling RNA synthesized in the presence of antinomycin D. During persistent infection the species of messenger RNA synthesized were similar in size and relative proportions to those seen during acute infection, but there were some minor differences. Full-sized B virion RNA was generally not detected during persistent infection, and new species (probably DI virion RNA) appeared.

Animals↗

PubMed1977

Antigenic shift of visna virus in persistently infected sheep.

Visna viruses isolated from persistently infected sheep were antigenically distinct from the plaque-purified virus used for inoculation. The selection of antigenic variants under antibody pressure, thought to occur in vivo, was reproduced in sheep cell cultures inoculated with plaque-purified visna virus and maintained in antibody. Antigenic shift may be a mechanism for persistence of virus in slow or recurrent viral infections.

Animals↗

PubMed1979

A comparative study of tick-borne encephalitis virus RNA synthesis in acutely and persistently infected cells.

Rate zonal and buoyant density gradient centrifugation did not reveal any difference between tick-borne encephalitis virus virions released from acutely or persistently infected cells. All three RNA species characteristic for flavivirus replication were found both in acutely or persistently infected cells, but increased levels of intracellular 42S RNA polyadenylation was observed in persistently infected cells.

Animals↗

PubMed1979

Pneumoviruses: the cell surface of lytically and persistently infected cells.

Human embryonic lung (MRC-5), feline embryo (FEA), mink lung (Mv1Lu) and monkey kidney (BSC-1) cells infected by respiratory syncytial virus showed characteristic morphological changes when viewed by scanning electron microscopy. The surfaces of respiratory syncytial virus-infected cells developed a profusion of slender filaments after 48 h incubation at 31 degrees C. Similar changes in surface morphology were observed in BSC-1 cells infected by murine pneumonia virus. Filament production therefore appears to be a common property of pneumo-viruses. Filaments were not observed in cells infected with either syncytial and non-syncytial herpes simplex virus, the cytocidal vesicular stomatitis and Batai (Bunyaviridae) viruses, or the focus-inducing rabbit fibroma virus. Filament production was not observed in cells infected with ts mutants of respiratory syncytial (RS) virus during incubation at the restrictive temperature, or in a persistently infected culture of BSC-1 cells at 37 degrees C. The persistently infected cells (the RS ts 1/BSC-1 line) had some of the characteristics of cells transformed by oncogenic viruses, namely ability to overlap adjacent cells and agglutination by a low concentration of concanavalin A. The pseudo-transformed phenotype was temperature-dependent, however, and suppressed by raising the temperature of incubation to 39 degrees C. The presence of virus antigen at the cell surface was similarly temperature-dependent in these cells, diminished at high temperature (39 degrees C) and enhanced at low temperature (31 degrees C), suggesting that the changes in the host cell were the result of insertion of virus protein into the cell membrane. Evidently, persistent infection by a cytoplasmic virus can produce alterations in the host cell usually associated with transformation by nuclear viruses.

Animals↗

PubMed2025

SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study.

BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold ≤30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0·0001) and individuals older than 60 years (p=0·0027). The median within-host genome-wide evolutionary rate was 7·9 × 10-4 substitutions per site per year (IQR 7·0-9·0 × 10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.

Humans↗