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Results for “Virus Replication”

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PubMed1996

Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication.

Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.

Cell Line↗

PubMed2005

VP40 octamers are essential for Ebola virus replication.

Matrix protein VP40 of Ebola virus is essential for virus assembly and budding. Monomeric VP40 can oligomerize in vitro into RNA binding octamers, and the crystal structure of octameric VP40 has revealed that residues Phe125 and Arg134 are the most important residues for the coordination of a short single-stranded RNA. Here we show that full-length wild-type VP40 octamers bind RNA upon HEK 293 cell expression. While the Phe125-to-Ala mutation resulted in reduced RNA binding, the Arg134-to-Ala mutation completely abolished RNA binding and thus octamer formation. The absence of octamer formation, however, does not affect virus-like particle (VLP) formation, as the VLPs generated from the expression of wild-type VP40 and mutated VP40 in HEK 293 cells showed similar morphology and abundance and no significant difference in size. These results strongly indicate that octameric VP40 is dispensable for VLP formation. The cellular localization of mutant VP40 was different from that of wild-type VP40. While wild-type VP40 was present in small patches predominantly at the plasma membrane, the octamer-negative mutants were found in larger aggregates at the periphery of the cell and in the perinuclear region. We next introduced the Arg134-to-Ala and/or the Phe125-to-Ala mutation into the Ebola virus genome. Recombinant wild-type virus and virus expressing the VP40 Phe125-to-Ala mutation were both rescued. In contrast, no recombinant virus expressing the VP40 Arg134-to-Ala mutation could be recovered. These results suggest that RNA binding of VP40 and therefore octamer formation are essential for the Ebola virus life cycle.

Animals↗

PubMed2003

[Influence of HGV super-infected with HIV or HCV on the virus replication].

OBJECTIVE: To realize human immunodeficiency virus(HIV) and hepatitis C virus(HCV) super-infected with hepatitis G virus(HGV or GBV/C) and to probe into the mechanism of these virus infection in the body. METHODS: HIV and HCV load were tested by the quantitated RT-PCR in the HIV or HCV infected plasma samples respectively and the HGV RNA was detected in all of the samples. Then some of the HGV positive were sequenced. RESULTS: 123 of 317 HIV patients were positive for HGV, the positive rate was 38.8%. Among the 91 HCV patients, 19 were positive for HGV. The positive rate is 20.9% which was less than that of HIV patients. HIV load of the patients super-infected with HGV was less than that of those without HGV[(1.8+/-0.6)x10 copies/ml compared with (1.9+/-1.1)x10(2)copies/ml]; while HGV and HCV super-infection did not influence the HCV RNA load significantly [(1.5+/-0.6)x10(4) copies/ml compared with (5.4+/-1.8)x10(4)copies/ml]. The HGV sequences from HIV or HCV patients were compared and showed no difference markedly. CONCLUSION: The rate of the HIV and HGV super-infection is higher than that of HCV. HGV may inhibit HIV reproduction in the body while superinfection.

GB virus C↗

PubMed1995

Interferon treatment inhibits virus replication in HIV-1- and SIV-infected CD4+ T-cell lines by distinct mechanisms: evidence for decreased stability and aberrant processing of HIV-1 proteins.

We have examined the effects of interferon (IFN)-alpha/beta on HIV-1 and SIV replication in CD4+ T-cell lines. To enable us to examine these effects on a single cycle of virus replication, cells were synchronously infected with HIV-1 LAI or SIV mac251. Cell lines included MT4 cells which were responsive to IFN and, as controls, C8166 cells which failed to respond to interferon treatment. Similar to previous reports, we found that replication of both HIV-1 and SIV was markedly inhibited in responsive MT4 cell lines treated with IFN. No such decreases were observed in HIV-1-infected, IFN-treated C8166 cells. Levels of both intracellular and extracellular viral antigens decreased in both HIV-1- and SIV-infected MT4 cells treated with IFN. Whereas steady state levels of viral-specific RNAs dramatically declined in SIV-infected cells, no such decrease was observed in IFN-treated HIV-1-infected cells. In accordance with these data, the rate of viral protein synthesis did not significantly change in HIV-1-infected, IFN-treated MT-4 cells. Western blot analysis of extracts prepared from IFN-treated HIV-1-infected cells revealed a decreased accumulation of most HIV-1-specific glycoproteins and proteins with the exception of the pr55 gag precursor. Pulse-chase experiments confirmed the enhanced stability of pr55 in IFN-treated cells, but also unexpectedly demonstrated the accelerated and quantitative processing of the p26 precursor (p24 capsid [CA] plus p2) to the final processed p24 (CA) polypeptide. These data, taken together, suggest that IFN deregulated viral protein processing and caused reduced protein stability in HIV-1-infected cells while inhibiting an earlier stage of replication in SIV-infected cells.

Animals↗

PubMed2002

Apoptosis induced in an early step of African swine fever virus entry into vero cells does not require virus replication.

Permissive Vero cells develop apoptosis, as characterized by DNA fragmentation, caspases activation, cytosolic release of mitochondrial cytochrome c, and flow cytometric analysis of DNA content, upon infection with African swine fever virus (ASFV). To determine the step in virus replication that triggers apoptosis, we used UV-inactivated virus, inhibitors of protein and nucleic acid synthesis, and lysosomotropic drugs that block virus uncoating. ASFV-induced apoptosis was accompanied by caspase-3 activation, which was detected even in the presence of either cytosine arabinoside or cycloheximide, indicating that viral DNA replication and protein synthesis were not required to activate the apoptotic process. The activation of caspase-3 was released from chloroquine inhibition 2 h after virus absorption, while the infection with UV-inactivated ASFV did not induce the activation of the caspase cascade. We conclude that ASFV induces apoptosis in the infected cell by an intracellular pathway probably triggered during the process of virus uncoating.

African Swine Fever Virus↗

PubMed1998

Herpes simplex type 1 induction of persistent NF-kappa B nuclear translocation increases the efficiency of virus replication.

The latent form of the dimeric transcription factor NF-kappa B is sequestered in the cytoplasm by proteins containing ankyrin repeats, such as 1 kappa B alpha and beta, or by the p105 precursor form of the NF-kappa B p50 subunit. Tumor necrosis factor alpha or virus infection can cause targeted destruction of 1 kappa B and nuclear translocation of NF-kappa B. Following translocation, NF-kappa B mediates immune, inflammatory, or anti-apoptotic responses. Here we present evidence that beginning at around 6 h postinfection, herpes simplex virus (HSV) induces a persistent translocation of NF-kappa B into the nucleus of C33 cells, coincident with loss of both 1 kappa B alpha and 1 kappa B beta. Translocation failed to occur when infecting virus was preincubated with neutralizing antibody to viral envelope glycoproteins gD or gH, thus preventing entry, or when cells infected with viruses expressing mutated forms of immediate-early regulatory proteins lCP4 or lCP27. Surprisingly, no increase in the trans-activation function of NF-kappa B, as assayed by transient expression of CAT, was detected following HSV infection. The significance of NF-kappa B nuclear translocation for virus replication was demonstrated by an 80-90% reduction in virus yield following infection of C33 cells expressing a constitutive repressor form of 1 kappa B alpha. Models that reconcile nuclear translocation of NF-kappa B with the inability to detect NF-kappa B-dependent gene expression are discussed.

Biological Transport↗

PubMed1976

Ultrastructure of mumps virus replication in organotypic cultures of hamster choroid plexus.

Organotypic cultures of newborn hamster choroid plexus were inoculated with equal titre doses of newly isolated or hamster adapted strains of mumps virus. The ultrastructure of virus replication in choroid epithelial cells of the cultures was compared. No qualitative differences were observed; however, the adapted strain produced significantly greater numbers of virions and earlier destruction of the cultures. These findings are consistent with previous in vivo observations of the ultrastructure of the replication of these strains in the newborn hamster central nervous system. This in vitro study leads further support to the hypothesis that differences in the in vivo biological effects of the virus strains are primarily the result of virus-cell rather than virus-host interactions.

Animals↗

PubMed1991

Restricted virus replication in the spinal cords of nude mice infected with a Theiler's virus variant.

The Daniels strain of Theiler's murine encephalomyelitis produces a chronic disease which is an animal model for human demyelinating disorders. Previously, we selected a neutralization-resistant virus variant producing an altered and diminished central nervous system disease in immunocompetent mice which was evident during the later stage of infection (after 4 weeks) (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). The exact epitope determining neurovirulence was precisely mapped to a capsid protein, VP-1, and represents a neutralizing region (A. Zurbriggen, J. M. Hogle, and R. S. Fujinami, J. Exp. Med. 170:2037-2049, 1989). Here, we present experiments with immunoincompetent animals to determine viral replication, spread, and targeting to the central nervous system in the absence of detectable antibodies or functional T cells. Nude mice were infected orally, and the virus was monitored by plaque assay, immunohistochemistry, and in situ hybridization. Early during the infection (1 week), the variant virus induced an acute disease comparable to that induced by the wild-type virus in these nude mice. Alterations in tropism in the central nervous system were not apparent when wild-type parental Daniels strain virus was compared with the variant virus. Moreover, variant virus replicated in tissue culture (BHK-21 cells) to similarly high titers in a time course identical to that of the wild-type virus (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). However, replication of the variant virus versus the wild-type virus within the spinal cord of athymic nude mice infected per os was substantially restricted by 6 weeks postinfection. Therefore, the reduced neurovirulence in the later stage (6 weeks) of the disease is most likely due to a diminished growth rate or spread of the variant virus in the central nervous system rather than to marked differences in viral tropism.

Animals↗

PubMed1979

Phosphonoformate inhibition of visna virus replication.

Phosphonoformate (PFA) inhibits multiplication of visna virus in sheep choroid plexus cells; a 50% reduction of virus yield was obtained by 20 to 80 microM PFA. Morphological changes, such as syncytial formation and cell degeneration, could be reversibly prevented by PFA. Cell growth was not significantly affected at 500 microM PFA, although prolonged treatment with 2 mM PFA did arrest cell growth. Cell-free reverse transcriptase activity primed with various synthetic template-primers was inhibited about 90% in the presence of 100 microM PFA. The results from kinetic experiments suggested that reverse transcriptase was utilized early but not late in the infection cycle. A structurally related substance, phosphonoacetate, did not inhibit visna virus multiplication and had no inhibitory effect on reverse transcriptase activity at a concentration of 500 microM.

Animals↗

PubMed2005

Correlation between type of adaptive immune response against porcine circovirus type 2 and level of virus replication.

Porcine circovirus 2 (PCV2) replication is characterized by high variation among infected pigs. This study investigated the role of immunologic responses in causing this variation. Twelve gnotobiotic pigs were inoculated with PCV2. Four of these pigs were treated with cyclosporin A (CysA) to monitor the effect of the adaptive immunity on the development of the PCV2 infection. Through lymph node biopsies at 10, 15, and 21 days postinoculation (DPI), PCV2 replication in lymphoid tissues was monitored. The production of total PCV2-specific and PCV2-neutralizing antibodies was followed, together with interferon-gamma (IFN-gamma) mRNA expression levels in peripheral blood monocytes as a marker for cellular immunity. In general, the CysA-treated pigs showed the highest PCV2 titers, indicating that the adaptive immunity is necessary to restrain PCV2 replication. Three different PCV2 replication patterns were observed in non-CysA-treated pigs. Pattern 1: In two pigs, PCV2 was not detected. They had the highest neutralizing antibody titers, appearing from 15 DPI. In these pigs a good cellular response was indicated by a peak in IFN-gamma mRNA at 15 DPI. Pattern 2: Five pigs contained low to moderate PCV2 titers at 15 DPI, remaining constant or decreasing towards 21 DPI. Lower neutralizing antibody titers were observed and no rise in IFN-gamma was detected. Pattern 3: In one pig, a low PCV2 titer at 15 DPI dramatically increased toward 21 DPI. Although an antibody response against PCV2 was mounted, no PCV2-neutralizing antibodies were detected. This pig also showed no rise in IFN-gamma. The study findings indicate that variation in the onset of the adaptive immunity may account for variation in PCV2 replication among pigs. Absence of PCV2-neutralizing antibodies may be an important factor in the development of an increased virus replication.

Animals↗

PubMed1986

Virus replication inhibitory peptide inhibits the conversion of phospholipid bilayers to the hexagonal phase.

Virus replication inhibitory peptide (carbobenzoxy-D-Phe-L-PheGly) was shown to be a potent specific inhibitor of the replication of paramyxovirus and myxovirus (Richardson, Scheid and Choppin (1980), Virology 105, 205-222). This peptide inhibits the membrane fusing activity of a viral glycoprotein. Many agents which promote the formation of the hexagonal phase in membranes also accelerate membrane fusion. At a mole fraction of 0.1, viral replication inhibitory peptide can raise the bilayer to hexagonal phase transition temperature of dielaidoylphosphatidylethanolamine by almost 10 degrees. Two related peptides, carbobenzoxy-L-PheGly and carbobenzoxy-L-GlyPhe, are less potent in raising the bilayer to hexagonal phase transition temperature, with the latter peptide being the least effective of the three. This order of potency is the same as the order of potency in inhibiting viral replication. Substances which inhibit hexagonal phase formation of pure lipids may also inhibit membrane fusion.

Calorimetry, Differential Scanning↗

PubMed1977

Virus-replicating T cells in the immune response of mice. I. Virus plaque assay of the lymphocytes reactive to sheep erythrocytes.

Virus plaque-forming cell assay with vesicular stomatitis virus (VSV), which had been originally introduced by Bloom and his colleagues as a tool for the enumeration of activated lymphocytes, was first applied to the immune response of mice to a widely used antigen, i.e. sheep red blood cells (SRBC). When spleen cells taken from mice previously primed with SRBC were cultured in the presence of the antigen, lymphocytes capable of replicating VSV (antigen-induced virus plaque-forming cells, Ag-V-PFC) were generated in the culture. They seemed to appear as early as 1 day of culture, and the peak was attained by the 2nd day. Most of Ag-V-PFC belonged to T-cell population, since 80-90% of Ag-V-PFC was killed by the treatment of cultured cells with anti-thymocyte serum plus complement. In vitro generation of Ag-V-PFC seemed to be highly cross-reactive (about 40%) with a related antigen (horse red blood cells). Ag-V-PFC detected in the present experiment may not represent helper T cells, effector T cells, or their precursors because of the following: (a) The generation of Ag-V-PFC was completely suppressed by the addition of anti-SRBC mouse serum in the culture, though the helper activity was apparently augmented by the same treatment. (b) Development of Ag-V-PFC was almost completely suppressed by the pretreatment of mice with cyclophosphamide 2 days before immunization, by which delayed-type hypersensitivity (DTH) was markedly augmented. (c) After the immunization of mice, Ag-V-PFC began to develop just when the level of DTH declined, at which point helper activity of the spleen cells also diminished. A possible role of Ag-V-PFC in the immune response was discussed.

Animals↗

PubMed1984

Comparative studies of rabies and Sindbis virus replication in human neuroblastoma (SYM-I) cells that can produce interferon.

K-104 cells, a cloned cell line derived from a human neuroblastoma (SYM-I), were induced by rabies HEP-Flury virus to release large amounts of interferon, and the resulting antiviral activity significantly suppressed the rabies virus replication. The role of endogenous interferon was confirmed by treatment with anti-interferon antibody which increased the yield of progeny virus. The virus yield in the second undiluted passage through K-104 cells was much less than that in the first passage, because of the antiviral state initiated by brief contact of interferon present in the virus inoculum with cells during the short period of virus adsorption. When the m.o.i. was relatively low, as in the third undiluted passage, the effect of interferon present in the inoculum was enhanced and most of the infected cells survived but were shown to be in a state of persistent infection. Defective interfering (DI) particles did not accumulate rapidly during these three undiluted passages. When Sindbis virus was used for infection, the endogenous interferon system of K-104 cells was not activated during 12 undiluted passages. However, on the 12th passage, the yield began to decline due to the generation and accumulation of DI particles.

Animals↗

PubMed1984

Acute type A hepatitis during chronic hepatitis B virus infection: association of depressed hepatitis B virus replication with appearance of endogenous alpha interferon.

Two patients with chronic type B hepatitis and intercurrent episodes of acute type A hepatitis are presented. Serological markers of hepatitis B virus replication decreased or became undetectable in both patients during the acute illness, while interferon activity was transiently detected in serum. The presence of serum leukocyte (alpha) interferon was confirmed by neutralization with specific antisera and tests of pH2 stability. These observations suggest a role for natural leukocyte (alpha) interferon in the modulation and control of hepatitis B virus infection and provide further evidence to support trials of exogenous leukocyte (alpha) interferon in the chronic infection.

Acute Disease↗

PubMed1998

Bovine viral diarrhea virus replication in bovine follicular epithelial cells derived from persistently infected heifers.

Bovine follicle fluid and oocytes surrounded by follicular epithelial (FE) cells were collected from ovaries of two heifers persistently infected with bovine viral diarrhea virus (BVDV). BVDV was present in the follicle fluid at a higher titer than in serum. The oocytes were matured in vitro under culture conditions of 39 degrees C in humidified air containing 5% CO2. In vitro fertilization was performed after 24 hr in culture (the day of insemination was defined as day 1), and culture was continued through day 10. BVDV was present in the culture medium at titers of 10(2.25) to 10(3.25) TC(I)D50/0.1 ml. The virus was also detected in FE cells collected on day 10. Viral antigen was demonstrated in the cytoplasm of FE cells by the indirect immunofluorescence technique. However, no BVDV was detected in the embryos on day 10. These findings suggested that the oocytes or embryos were unlikely to be infected with BVDV, but that the FE cells were infected with BVDV and supported virus replication in cattle persistently infected with BVDV.

Animals↗

PubMed2002

In vitro characterization of A-315675, a highly potent inhibitor of A and B strain influenza virus neuraminidases and influenza virus replication.

A-315675 is a novel, pyrrolidine-based compound that was evaluated in this study for its ability to inhibit A and B strain influenza virus neuraminidases in enzyme assays and influenza virus replication in cell culture. A-315675 effectively inhibited influenza A N1, N2, and N9 and B strain neuraminidases with inhibitor constant (K(i)) values between 0.024 and 0.31 nM. These values were comparable to or lower than the K(i) values measured for oseltamivir carboxylate (GS4071), zanamivir, and BCX-1812, except for the N1 enzymes that were found to be the most sensitive to BCX-1812. The time-dependent inhibition of neuraminidase catalytic activity observed with A-315675 is likely due to its very low rate of dissociation from the active site of neuraminidase. The half times for dissociation of A-315675 from B/Memphis/3/89 and A/Tokyo/3/67 (H3N2) influenza virus neuraminidases of 10 to 12 h are significantly slower than the half times measured for oseltamivir carboxylate (33 to 60 min). A-315675 inhibited the replication of several laboratory strains of influenza virus in cell culture with potencies that were comparable or superior to those for oseltamivir carboxylate and BCX-1812, except for the A/H1N1 viruses that were found to be two- to fourfold more susceptible to BCX-1812. A-315675 and oseltamivir carboxylate exhibited comparable potencies against a panel of A/H1N1 and A/H3N2 influenza virus clinical isolates, but A-315675 was found to be significantly more potent than oseltamivir carboxylate against the B strain isolates. The favorable in vitro results relative to other clinically effective agents provide strong support for the further investigation of A-315675 as a potential therapy for influenza virus infections.

Acetamides↗

PubMed1982

Differential effect of prostaglandins and other products of arachidonic acid metabolism on measles virus replication in Vero cells.

The influence of cyclic adenosine 3', 5'-monophosphate (cAMP) and prostaglandin (PG), E1, E2, F2 alpha, A2 and thromboxane B2 (TxB2) and measles virus infection was investigated. Addition of PGE1, E2 and cAMP (10(-3)-10(-)8M) inhibited measles virus replication in Vero cells. TxB2 and PGA2 enhanced replication. Cytotoxic effects were not observed. Inhibition of infectious titers (98%) was most pronounced when agents were present throughout replication. Treated cells exhibited hemadsorbing antigen, but the size and number of cytoplasmic inclusions was decreased by cAMP. Pre-treatment of cells with PGE1 or presence of PGE1 during virus adsorption enhanced infectious titers (30%). Results suggest that cAMP and PGE1 inhibit measles virus production infection. That both enhancing and inhibiting effects of PGs were seen suggest that measles virus may require PG at specific times during the replicative cycle.

Animals↗

PubMed1981

Biological properties of an influenza A virus-specific killer T cell clone. Inhibition of virus replication in vivo and induction of delayed-type hypersensitivity reactions.

We tested two biological properties of a continuously growing mouse cytotoxic T cell line, L4, which is specific for influenza A virus and has been cloned and recloned many times. We previously reported that L4 cells are H-2 restricted and cross-reactive for all type A influenza viruses, whereas they do not recognize type B influenza viruses. They bear Thy-1 and Lyt-2 markers. In the present study, we show that L4 cytotoxic T cells protect mice against a lethal influenza infection on transfer to syngeneic recipients, and reduce virus titers in the lungs of mice challenged with a heterologous type A influenza virus. This provides further support for the active role of cytotoxic T cells in limiting virus replication in influenza infection. We could also demonstrate that the cloned cytotoxic T cells induce a delayed-type hypersensitivity skin reaction in the footpads of mice challenged with live or inactivated influenza virus. This reaction can be observed at 24 h, but has declined by 48 h. A clone of cells derived from L4 that has lost its cytotoxic potential and its ability to recognize infected cells did not induce a delayed-type hypersensitivity reaction in the presence of virus. Thus, cytotoxic T cells actively killing influenza virus-infected cells are able to induce a delayed-type hypersensitivity skin reaction to homologous and heterologous type A influenza viruses.

Animals↗