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At least 1,261 records · Page 70Linked to original sources
PubMed1999

HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy.

Therapeutic intervention with highly active antiretroviral therapy (HAART) can lead to suppression of HIV-1 plasma viremia to undetectable levels for 3 or more years. However, adherence to complex drug regimens can prove problematic, and subjects may temporarily discontinue HAART for variable periods. We studied 6 HIV-1-infected individuals who stopped therapy. Off HAART, levels of viremia were suppressed to fewer than 500 copies/mL in 2 subjects for more than 12 and more than 24 months, respectively, and in 1 subject for 4 months on 1 occasion. Three subjects failed to contain plasma viremia. Broad and strong HIV-1-specific immune responses were detected in subjects with prolonged suppression of viral replication. This longitudinal study suggests that containment of HIV-1 replication to low or undetectable levels after discontinuation of HAART is associated with strong virus-specific immune responses. Boosting of HIV-1-specific immune responses should be considered as an adjunctive treatment strategy for HIV-1-infected individuals on HAART.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Localization and biochemical characterization of alfalfa mosaic virus replication complexes.

Replication complexes were isolated from alfalfa mosaic virus-infected tobacco protoplasts. Most of the RNA-synthesizing activity appears to colocalize with the intact chloroplasts upon sucrose-gradient centrifugation of cellular homogenates. Further analysis of these replication complexes showed that the enzyme is strongly associated with the outside of the chloroplasts, the endogenous template being well protected against ribonuclease action. RNA polymerase activity is sensitive to protease treatment of intact chloroplast fraction showing that an essential part of the enzyme complex is facing the in vitro medium, and probably the cytosol in vivo.

Cell Compartmentation↗
PubMed2004

A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties.

Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2'-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5'-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2'-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2'-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2'-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.

Animals↗
PubMed1999

Measles virus replication in cells of myelomonocytic lineage is dependent on cellular differentiation stage.

Measles virus (MV)-infected monocytes may have a central role in virus-induced immunosuppression. Our understanding of MV replication in monocytic cells is, however, incomplete. In this work we have investigated MV replication in cells of human myelomonocytic lineage with different maturation stages in order to study the effect of cellular maturation on virus infection. MV was able to infect human bone marrow myeloid granulocyte-macrophage colony-forming cells (CFC-GM) as well as monocytes and macrophages, but the replication cycle seemed to be regulated by the maturation stage of the cells. Virus infection in CFC-GM was productive, unlike in monocytes and macrophages, where an extensive viral RNA synthesis occurred and high amounts of proteins were synthesised without a remarkable release of infectious virus. Efficiency of viral macromolecular synthesis in macrophages was comparable to that of promonocytic cell line U-937 and human epithelial cell line A549, but in contrast to macrophages the cell lines highly supported productive infection. On the other hand, chemically induced maturation of the human promyelocytic and promonocytic cell lines HL-60, THP-1, and U-937 to more mature macrophage-like forms did not markedly alter the replication cycle of MV in these cell lines. Our results showed that MV replication in myelomonocytic cells varied depending on the maturation stage of the cells. The immature myelomonocytic cells supported productive virus infection, but the maturation process lead to cellular changes that caused a restriction of MV replication cycle partly at posttranscriptional and partly at posttranslational level. The metabolic milieu of monocytes and macrophages as such was sufficient to support extensive viral macromolecular synthesis.

Blotting, Western↗
PubMed2002

Cellular protein binds to sequences near the 5' terminus of potato virus X RNA that are important for virus replication.

The sequences in the 5'-nontranslated region (NTR) of Potato virus X (PVX) genomic RNA were previously reported to contain several regulatory elements that are required for genomic and subgenomic RNA accumulation. To investigate whether cellular proteins bind to these elements, we conducted electrophoretic mobility shift assays (EMSA) with protoplast protein extracts and RNA sequences from the PVX 5'-NTR. These analyses showed that the 5' region of PVX positive-strand RNA formed complexes with cellular proteins. UV cross-linking studies of complexes formed with various deletions of the PVX RNA indicated that a 54-kDa cellular protein (p54) was bound to nt 1-46 at the 5' terminus of PVX RNA. Site-directed mutations introduced within this 46-nt region further indicated that an ACCA sequence element located at nt 10-13 was important for optimal binding. In addition, mutations that decreased the affinity of the template RNA for the cellular factor decreased PVX plus-strand RNA accumulation in protoplasts. These studies suggest that the p54 may function in PVX RNA replication by binding to the 5' terminus of the viral genomic RNA.

5' Untranslated Regions↗
PubMed1992

Hepatitis C virus replication during acute infection in the chimpanzee.

The events following experimental infection of 2 chimpanzees with the H strain of hepatitis C virus (HCV) were studied by quantitating the levels of HCV RNA in liver and serum. Serum and liver samples were tested every 1-3 weeks for up to 32 weeks. The genomic and antigenomic strands of HCV RNA were individually detected in liver and serum by strand-specific reverse transcription followed by polymerase chain reaction (PCR) using nested primers specific for the 5' noncoding region of the HCV genome and were quantitated by end-point dilution of the nucleic acid extract. Both genomic and antigenomic strands were detected in liver and serum within 1 week after inoculation and approximately 1 week before the development of elevated levels of alanine aminotransferase (ALT) activity. Changes in levels of antigenomic strand paralleled those of the genomic strand in both serum and liver. Titers of HCV RNA in serum and liver generally correlated with changes in ALT levels.

Acute Disease↗
PubMed2000

Long-term protection against bovine leukaemia virus replication in cattle and sheep.

In this report, we have evaluated the ability of two different types of live attenuated bovine leukaemia virus (BLV) variants (BLV DX and BLV 6073) to protect cattle and sheep against a heterologous wild-type BLV challenge. Four months after challenge, the protection of the vaccinated animals was effective in contrast to unvaccinated controls. However, long-term protection (18 months after challenge) was observed only in six out of seven animals, one of the vaccinated cattle being infected 12 months after challenge. A second prospective approach investigated the injection of naked plasmid DNA. Two sheep were injected with plasmid DNA encoding the BLV envelope proteins; the challenge virus infection was delayed but could not be completely abrogated. Our results demonstrate that vaccines based on live attenuated viruses and naked DNA injections are able to delay BLV infection, although complete protection cannot be achieved. In addition, our data cast light onto the need to perform long-term vaccination trials because challenge superinfection can occur even after apparent protection for 12 months.

Animals↗
PubMed2005

Borna disease virus replication in organotypic hippocampal slice cultures from rats results in selective damage of dentate granule cells.

In the hippocampus of Borna disease virus (BDV)-infected newborn rats, dentate granule cells undergo progressive cell death. BDV is noncytolytic, and the pathogenesis of this neurodevelopmental damage in the absence of immunopathology remains unclear. A suitable model system to study early events of the pathology is lacking. We show here that organotypic hippocampal slice cultures from newborn rat pups are a suitable ex vivo model to examine BDV neuropathogenesis. After challenging hippocampal slice cultures with BDV, we observed a progressive loss of calbindin-positive granule cells 21 to 28 days postinfection. This loss was accompanied by reduced numbers of mossy fiber boutons when compared to mock-infected cultures. Similarly, the density of dentate granule cell axons, the mossy fiber axons, appeared to be substantially reduced. In contrast, hilar mossy cells and pyramidal neurons survived, although BDV was detectable in these cells. Despite infection of dentate granule cells 2 weeks postinfection, the axonal projections of these cells and the synaptic connectivity patterns were comparable to those in mock-infected cultures, suggesting that BDV-induced damage of granule cells is a post-maturation event that starts after mossy fiber synapses are formed. In summary, we find that BDV infection of rat organotypic hippocampal slice cultures results in selective neuronal damage similar to that observed with infected newborn rats and is therefore a suitable model to study BDV-induced pathology in the hippocampus.

Animals↗
PubMed2002

[Ani immunomodulator Hepon inhibits hepatitis C virus replication in human cell cultures in vitro].

Antiviral activity of immunomodulator "Hepon" was evaluated in human cells culture infected with hepatitis C virus. "Hepon" presence protected human cells SW-13 from cytopathogenic effect of hepatitis C virus. Maximum antiviral effect was demonstrated by "Hepon" at concentration 1 mcg/mL. Control antiviral agent reaferon (interferon alfa-2a) was more potent as vitality protecting agent in the case of SW-13 human cells culture. "Hepon" activity is based on changes of cytokins and interferons spectrum so this immunomodulator is expected to be effective against different viruses including herpes virus and encephalocarditis virus.

Adjuvants, Immunologic↗
PubMed1984

Effect of coumermycin on influenza A virus replicative cycle.

Coumermycin A1, a Novobiocin related antibiotic, has been tested in vivo and in vitro for its activity on Influenza A viruses. In a range of concentrations between 3 and 5 micrograms/ml virus production was drastically reduced. The drug was able to inhibit virus release into culture medium also if added up to the sixth hour following infection and its action was reversible within this time. The synthesis of virus induced polypeptides was generally depressed but production of the HA was more deeply inhibited. Viral transcriptase activity in vitro was also affected by the presence of Coumermycin A1 but at doses which seem to high to consider this event as a phenomenon likely to play a role in vivo. It is suggested that the antiviral activity of the drug is mediated by the inhibition of the host cell metabolism.

Aminocoumarins↗
PubMed1996

[Appearance of hepatitis C virus replication and increase of aminotransferase activity after corticoid treatment of presumed autoimmune hepatitis. 2 cases].

Autoimmune-related and hepatitis C virus-related chronic hepatitis are sometimes difficult to differentiate. We report two cases of chronic hepatitis with high levels of serum anti-smooth muscle antibodies, positive hepatitis C virus serology, and negative serum RNA, which were first treated with corticotherapy. Both patients responded with marked increases in aminotransferase levels, and positive RNA. The first case may have been type 1 autoimmune hepatitis with hepatitis C virus infection, and the second chronic hepatitis C with positive serum auto-antibodies. The increase in viral antigen expression on the surface of the hepatocytes following corticosteroid treatment may have favoured a direct cytopathogenic effect of hepatitis C virus.

Aged↗
PubMed1999

Nonstructural C protein is required for efficient measles virus replication in human peripheral blood cells.

The P gene of measles virus (MV) encodes the phosphoprotein, a component of the virus ribonucleoprotein complex, and two nonstructural proteins, C and V, with unknown functions. Growth of recombinant MV, defective in C or V expression, was explored in human peripheral blood mononuclear cells (PBMC). The production of infectious recombinant MV V- was comparable to that of parental MV tag in simian Vero fibroblasts and in PBMC. In contrast, MV C- progeny was strongly reduced in PBMC but not in Vero cells. Consistently, the expression of both hemagglutinin and fusion proteins, as well as that of nucleoprotein mRNA, was lower in MV C--infected PBMC. Thus, efficient replication of MV in natural host cells requires the expression of the nonstructural C protein. The immunosuppression that accompanies MV infection is associated with a decrease in the in vitro lymphoproliferative response to mitogens. MV C- was as potent as MV tag or MV V- in inhibiting the phytohemagglutinin-induced proliferation of PBMC, indicating that neither the C protein nor the V protein is directly involved in this effect.

Animals↗
PubMed2025

Viral hijacking of host DDX60 promotes Crimean-Congo haemorrhagic fever virus replication via G-quadruplex unwinding.

Crimean-Congo haemorrhagic fever virus (CCHFV) is the most prevalent tick-borne zoonotic bunyavirus, causing severe hemorrhagic fever and fatality in humans. Currently, the absence of approved vaccines or therapeutics for CCHFV infection necessitates the development of innovative therapeutic strategies. Here, we identify a guanine (G)-rich sequence located within the mRNA of the glycoprotein precursor in the medium (M) segment of the CCHFV genome, designated as M-PQS-1664(+). M-PQS-1664(+) can form stable G-quadruplex (G4) structure and functions as a negative regulatory element for viral replication. Host DDX60 is up-regulated in response to CCHFV infection, thereby it is hijacked to unwind M-PQS-1664(+) G4 for facilitating viral replication. The FDA-approved drug Cepharanthine (CEP), which competes with DDX60 to specifically stabilize M-PQS-1664(+) G4 without a global induction of host cellular G4s formation, exhibits remarkable antiviral activity in vitro and in vivo. More importantly, CEP possesses antiviral activity (50% inhibitory concentration ~ 0.2 μM) that having ~ 88 × the potency of ribavirin. Our findings underscore the CCHFV G4s as a promising target for drug development and highlight the significant potential of CEP in combating CCHFV.

Hemorrhagic Fever Virus, Crimean-Congo↗
PubMed1986

In vivo study of the mechanism of action of antiviral agents against hepadna virus replication in the liver. Resistance of supercoiled viral DNA.

The mode of action of antiviral agents (interferon and adenine arabinoside) was studied in human and in animals chronically infected with hepadna virus. Interferon (36-100 megaunits) was given to 20 carrier patients, and hepatitis B virus (HBV)-DNA replicative forms were studied in pre- and post-treatment biopsies. ARA-A was given intravenously to duck hepatitis B virus (DHBV)-infected ducks. Changes in intrahepatic viral replicative forms were studied by Southern blotting using 32P-labelled HBV or DHBV probe. Our study indicates that both interferon and ARA-A seem to effectively decrease 'mature' forms of viral DNA by an effect on either mRNA or DNA polymerase. However, the supercoiled viral DNA tends to resist the treatment, and may become the transcribing template for a new cycle of viral replication after cessation of the drugs.

Animals↗
PubMed1987

Analysis of brome mosaic virus replication and aminoacylation functions by site-specific mutagenesis.

Brome Mosaic Virus (BMV) has a tripartite RNA genome; each RNA and the subgenomic RNA encoding the viral coat protein share a highly homologous region of about 200 nucleotides at the 3' end, for which a tRNA-like structure has been proposed. Several sequences encoding functions, including replicase binding, initiation of (-) strand synthesis and tyrosine esterification are known to be nested within this region. Elongation factor EF-1 alpha binds to aminoacylated viral RNAs, but not to the uncharged forms. An additional function of the tRNA-like structure is to serve as a substrate for nucleotidyl transferase, which adds the terminal adenosine residue to the (+) sense virion RNAs. A template-dependent and template-specific replicase preparation from BMV-infected barley leaves has been characterized and extensively used for replication studies in vitro that complement studies in vivo using protoplasts. The replicase has been shown to initiate de novo both (-) strand synthesis on supplied (+) strand RNAs, and (+) strand subgenomic RNA synthesis on supplied (-) sense RNA3 templates. RNA transcripts obtained by transcription in vitro of cDNA clones containing desired base substitutions and deletions, have been supplied as templates for replication, aminoacylation and other assays. Use of such mutant RNAs has allowed the promoters for both (-) strand synthesis and for synthesis of the subgenomic (+) strand RNA to be characterized and defined. The same approach has also been used to reveal regions of the tRNA-like structure involved in the tyrosylation of the BMV RNAs. These experiments showed that, although regions important in aminoacylation and replication functions overlap, they are not identical. Some of the mutations tested in vitro have also been tested for infectivity in vivo using both barley plants and protoplasts. Mutants retaining replicase and nucleotidyl transferase template activity, but having lost aminoacylation capability are of special interest in that they should reveal the role of aminoacylation in the infection process.

Base Sequence↗
PubMed2001

Non-cytolytic inhibition of hepatitis B virus replication in human hepatocytes.

BACKGROUND/AIMS: Interferon-gamma (IFN-gamma) has been shown to abolish hepatitis B virus (HBV) gene expression and replication in HBV transgenic mice without destroying infected hepatocytes. We investigated the characteristics of IFN-gamma induced non-cytolytic inhibition of viral replication in human HBV infection. METHODS: We used an in vitro model where lymphocytes from 15 HBsAg positive patients were co-cultured with transfected hepatocytes supporting HBV replication. The effector and target cells were separated by a membrane, which allowed transfer of soluble factors only, to determine whether IFN-gamma produced from antigen-specific CD4+ T cells or mitogen stimulated lymphocytes inhibits HBV replication. RESULTS: IFN-gamma produced following lymphocyte stimulation reduced cytoplasmic HBV DNA in the target cells. The degree of HBV DNA reduction correlated with the level of IFN-gamma in the supernatants. Further investigations using naturally infected human hepatocytes confirmed that recombinant IFN-gamma reduces HBV DNA and HBV RNA in these cells as well, in parallel with the induction of cellular interferon-responsive genes. This antiviral effect was without significant cytotoxicity and was more pronounced in hepatocytes from patients with low HBV replication. CONCLUSIONS: These results provide direct evidence that IFN-gamma can inhibit both HBV transcription and replication in human hepatocytes without cell lysis.

Adult↗
PubMed2004

Viral Bcl-2 homologs and their role in virus replication and associated diseases.

Cellular Bcl-2 family proteins regulate a critical step in the mammalian programmed cell death pathway by modulating mitochondrial permeability and function. Bcl-2 family proteins are also encoded by several large DNA viruses, including all known gamma herpesviruses, adenoviruses, and several other unrelated viruses. Viral Bcl-2 proteins can prevent cell death but often escape cellular regulatory mechanisms that govern their cellular counterparts. By evading the "altruistic" suicide of infected cells, viruses can ensure replication and propagation in the infected host, but sometimes in surprising ways. Many human cancers and other disorders are associated with viruses that encode Bcl-2 homologs. Here we consider the available mechanistic data for viral compared to cellular Bcl-2 protein function along with relevance to the virus life cycle and human disease states.

Apoptosis↗