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PubMed2002

Selectable subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh7 cells.

Dicistronic, selectable subgenomic replicons derived from the Con1 strain of hepatitis C virus (HCV) are capable of autonomous replication in cultured Huh7 cells (Lohmann et al., Science 285:110-113, 1999). However, adaptive mutations in the NS3, NS5A, and/or NS5B proteins are required for efficient replication of these RNAs and increase by orders of magnitude the numbers of G418-resistant colonies selected following transfection of Huh7 cells. Here, we demonstrate that a subgenomic replicon (NNeo/3-5B) derived from an infectious molecular clone of a second genotype 1b virus, HCV-N (Beard et al., Hepatology 30:316-324, 1999) is also capable of efficient replication in Huh7 cells. G418-resistant cells selected following transfection with NNeo/3-5B RNA contained abundant NS5A antigen and HCV RNA detectable by Northern analysis. Replicon RNA in one of three clonally isolated cell lines contained no mutations in the NS3-NS5B polyprotein, confirming that adaptive mutations are not required for efficient replication in these cells. However, the deletion of a unique 4-amino-acid insertion that is present within the interferon sensitivity-determining region (ISDR) of the NS5A protein in wild-type HCV-N drastically decreased the number of G418-resistant colonies obtained following transfection of Huh7 cells. This effect could be reversed by inclusion of a previously described Con1 cell culture-adaptive mutation (S2005-->I), confirming that this natural insertion has a controlling role in determining the replication capacity of wild-type HCV-N RNA in Huh7 cells. Additional selectable, dicistronic RNAs encoding NS2-NS5B, E1-NS5B, or the full-length HCV polyprotein were also capable of replication and gave rise to G418-resistant cell clones following transfection of Huh7 cells. We conclude that RNA derived from this documented infectious molecular clone has a unique capacity for replication in Huh7 cells in the absence of additional cell culture-adaptive mutations.

Amino Acid Sequence↗
PubMed1990

Macrophages as susceptible targets for HIV infection, persistent viral reservoirs in tissue, and key immunoregulatory cells that control levels of virus replication and extent of disease.

Although macrophages are major targets for human immunodeficiency virus (HIV) infection in vivo, study of HIV-macrophage interactions in vitro was hindered because many laboratory strains of HIV would not replicate in macrophages, and because survival of macrophages in culture was poor. Addition of purified macrophage colony-stimulating factor (M-CSF) to cultured macrophages markedly improves their survival, but does not induce proliferation. HIV isolates that replicate in macrophages will also replicate in lymphocytes; however, isolates adapted to lymphoid cells (such as HIV-HTLVIIIB) will not replicate in macrophages. The envelope gene appears to be a major determinant of the cell tropism of viral isolates. T-cell grown virus stocks synthesize abundant gp120, while virus grown in macrophages contains relatively much less gp120. Electron microscopy of virions from macrophages shows them to be depleted of gp120 surface "spikes." Recombination studies show that the portion of the genome coding for the envelope glycoprotein appears to determine cell tropism. Lastly, rsCD4 neutralized macrophage-tropic isolates less efficiently than T-cell tropic isolates. HIV replication in macrophages is partially under the control of cellular factors, although these have been less well characterized than they have in lymphocytes.

Disease Susceptibility↗
PubMed1985

Effects of suramin on HTLV-III/LAV infection presenting as Kaposi's sarcoma or AIDS-related complex: clinical pharmacology and suppression of virus replication in vivo.

Suramin was given to ten outpatients with acquired immunodeficiency syndrome (AIDS) presenting as Kaposi's sarcoma (KS) or as an AIDS-related complex (ARC). Side-effects associated with the administration of 6.2 g of suramin over 5 weeks included fevers, rashes, urinary abnormalities, and transient rises in hepatic aminotransferases. Peak serum levels of over 100 micrograms/ml were attained. There was evidence of HTLV-III infectivity and replication in lymphocytes from four patients before therapy. The detectable virus level fell in each case by the time of the last dose, and in three cases it became undetectable at the end of therapy. In each case, viral replication was again detected in the weeks or months following the administration of suramin. Despite this in-vivo virustatic effect, no significant clinical or immunological improvement was observed using this short-term regimen. However, the results provide a rationale for investigating longer-term regimens.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Activation of human monocyte--derived macrophages with lipopolysaccharide decreases human immunodeficiency virus replication in vitro at the level of gene expression.

Activation of T lymphocytes infected with the human immunodeficiency virus-1 (HIV-1) results in enhancement of viral replication mediated in part by activation of cellular NF kappa B capable of binding directly to sequences in the viral long terminal repeat, or LTR. Together with CD4+ T cells, macrophages constitute a major target for infection by HIV-1. Unlike lymphocytes, however, stimulation of mononuclear phagocytes is not associated with cell division and proliferation. Human monocyte-derived macrophages transfected with HIV-LTR-CAT constructs demonstrated down-regulation of CAT activity after stimulation with bacterial lipopolysaccharide (LPS) that mapped to a region distinct from NF kappa B binding sites. In contrast, fresh monocytes and the promonocytic U937 cell line both demonstrated up-regulation of HIV-LTR-CAT expression by LPS. Differentiation of U937 by PMA to establish a nondividing phenotype resulted in down-regulation of transfected HIV-LTR-CAT activity by LPS similar to that in mature macrophages. Human monocyte-derived macrophages infected with HIV-1 in vitro demonstrated a decrease in viral p24 release after incubation in LPS that was comparable to the negative regulation that occurred in the transient transfection assays. Factors controlling HIV replication may differ in dividing and nondividing hematopoietic cells and may contribute to restricted viral expression in nondividing cells.

Cells, Cultured↗
PubMed2005

Divergent activities of interferon-alpha subtypes against intracellular hepatitis C virus replication.

BACKGROUNDS: Interferon (IFN)-alpha is represented by several structurally related subtypes that show different antiviral and anti-tumor effects. Here, we analyzed differential effects of IFN-alpha subtypes on intracellular hepatitis C virus (HCV) replication using HCV subgenomic replicon system as a model. METHODS: Huh7 and HeLa cells supporting expression of HCV replicon were treated with various concentrations of five recombinant human IFN-alpha subtypes 1, 2, 5, 8, and 10, and with IFN-alpha con1. The effects of IFNs on various cell-signaling pathways were assayed by using ISRE-, GAS-, AP1-, NF-kappa B-, CRE-, and SRE-luciferase reporter plasmids. RESULTS: Each IFN-alpha subtype suppressed HCV replication in a dose-dependent manner. Among them, IFN-alpha8 was the most effective, while IFN-alpha1 was the least effective with 50% inhibitory concentrations of 0.123IU/ml versus 0.375IU/ml, respectively. These differential effects against HCV replication did not correlate with levels of the IFN-responsive ISRE or GAS reporter activities, nor they did activate the other reporters, AP1, NF-kappa B, CRE and SRE. CONCLUSION: There were divergent effects of IFN-alpha subtypes against HCV replication that may be through JAK-STAT-independent pathways. Exploring further mechanisms of action may elucidate IFN-mediated cellular antiviral mechanisms.

Journal Article↗
PubMed2004

Influence of mutations in the hepatitis B virus genome on virus replication and drug resistance--implications for novel antiviral strategies.

Persistent infection with the hepatitis B virus (HBV) represents a major health problem worldwide with over 350 million patients at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double-stranded DNA virus with four overlapping genes and a unique life cycle, creating an intracellular pool of covalently closed circular DNA molecules for persistence and an RNA template for replication via reverse transcription. Mutations occur frequently, and particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antivirals), readily select escape mutants. For example, HBeAg-negative chronic HBV infection with either basal core promoter or precore mutations is predominant in many parts of the world. Therapy of HBV infection with the nucleoside analogue lamivudine frequently leads to the selection of drug-resistant strains with polymerase mutations. Treatment options for chronic HBV infection include at present either interferon-alpha or the oral nucleos(t)ide analogues lamivudine or adefovir. However, these drugs have drawbacks, including possible serious side effects and low response rates in HBeAg-negative patients in the case of interferon or recurrence of viremia after cessation of therapy and development of escape mutants after a long period of treatment with nucleoside inhibitors. Recent advances of in vitro and in vivo models allow to study new antiviral strategies, including novel nucleoside analogues, nucleocapsid inhibitors or small interfering RNA. This review summarises the impact of clinically relevant mutations in the HBV genome on viral replication and drug sensitivity, the current status of therapy and promising future perspectives on novel drug regimens.

Animals↗
PubMedDate not supplied

Inhibitory effect of a cyclic urea derivative on rubella virus replication.

1-(4-Morpholinomethyl)-tetrahydro-2(1H)-pyrimidinone (mopyridone) exhibited a marked activity against rubella virus (Judith and RA27/3 strains), a MIC50 value of 0.9 microM and selectivity ratio of 557.7 been found in the case of Judith strain. These data, in addition to the previous ones about its anti-alphavirus effects suggest the compound to be considered as a broad spectrum inhibitor of togavirus replication.

Animals↗
PubMed2005

Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes.

Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.

AIDS Vaccines↗
PubMed2000

Delta(12)-prostaglandin J(2) is a potent inhibitor of influenza A virus replication.

9-Deoxy-Delta(9),Delta(12)-13,14-dihydro-prostaglandin D(2) (Delta(12)-PGJ(2)), a natural cyclopentenone metabolite of prostaglandin D(2), is shown to possess therapeutic efficacy against influenza A virus A/PR8/34 (H1N1) infection in vitro and in vivo. The results indicate that the antiviral activity is associated with induction of cytoprotective heat shock proteins and suggest novel strategies for treatment of influenza virus infection.

Animals↗
PubMedDate not supplied

[Change in the sensitivity of influenza virus, replicating in the presence of rimantadine, to antiviral agents].

A variant obtained by a single passage of the initial FPV in the presence of 25 micrograms/ml rimantadine is more resistant to the drug than the parental virus. Sensitivity to rimantadine is higher in a variant obtained similarly by cell culture infection with rimantadine-resistant FPV. Potentiation of the antiviral effect of a combination of ribavirin (12-25 micrograms/ml) and rimantadine (0.1-6 micrograms/ml) is decreased or null if rimantadine dose is increased to 12-25 micrograms/ml; this phenomenon does not depend on the sensitivity of infective virus to rimantadine. Antiviral effect of drug combination with a high concentration of rimantadine is due to ribavirin alone.

Animals↗
PubMed1976

Inhibition of vaccinia virus replication in skin of tuberculin-sensitized animals challenged with PPD.

Induction of a celayed-type hypersensitivity reaction in tuberculin-sensitized animals by tuberculin purified protein derivative (PPD) at the site of dermal vaccinia virus (VV) infection markedly accelerated elimination of VV and led to clinical recovery. Viral titers were depressed by over 99.9% in the skin of animals given PPD as compared to animals given phosphate-buffered saline or nonspecific irritants. Low concentrations of acid labile interferon were found in the skin of uninfected tuberculin-sensitized animals challenged with PPD. High concentrations of acid stable interferon were found in skin of tuberculin-sensitized animals infected with VV and challenged with either PPD or PBS. The time of appearance of the acid stable interferon was markedly accelerated, however, in the animals challenged with PPD as compared with PBS. It is concluded that recovery from dermal vaccinia infection can be enhanced by induction of a local delayed-type hypersensitivity reaction with an antigen untelated to the infecting virus.

Animals↗
PubMed2003

A multifunctional turnip crinkle virus replication enhancer revealed by in vivo functional SELEX.

The motif1-hairpin (M1H), located on (-)-strands of Turnip Crinkle Virus (TCV)-associated satellite RNA C (satC), is a replication enhancer and recombination hotspot. Results of in vivo genetic selection (SELEX: systematic evolution of ligands by exponential enrichment), where 28 bases of the M1H were randomized and then subjected to selection in plants, revealed that most winners contained one to three short motifs, many of which in their (-)-sense orientation are found in TCV and satC (-)-strand promoter elements. Ability to replicate in protoplasts correlated with fitness to accumulate in plants with one significant exception. Winner UC, containing only a seven-base replacement sequence, was the second most fit winner, yet replicated no better than a 28-base random replacement sequence. Fitness of satC containing different M1H replacement sequences could be due to enhanced satC replication or enhanced ability to affect TCV movement, since satC interferes with TCV virion accumulation, which is correlated with enhanced movement to younger tissue. Cells inoculated with TCV and UC accumulated fewer virions when compared to other winners that replicated better in protoplasts but were less fit in plants. UC, and other first and second round winners, contained structures that were on average 33% more stable in their (+)-strand orientation, and most formed hairpins with a A-rich sequence at the base. These results suggest that M1H replacement sequences contribute to the fitness of satC by either containing (-)-strand elements that enhance satRNA replication and/or a (+)-strand hairpin flanked with single-stranded sequence that enhances TCV movement.

Base Sequence↗
PubMed1998

[Antisense oligodeoxynucleotide targeted at the pre-s region of DHBV could inhibit virus replication in vivo].

To study the antiviral effect of antisense oligodeoxynucleotide (AS-ODN), AS-ODN phosphotioates targeted to DHBV Pre-S region (951-968nt) (5'-TATCTCCTCCATTGTTTG-3') was synthesized. Two day-old ducklings were infected i.p. with 150 microliters of DHBV (3 x 10(8) copies/ml DHBV). After 12 days, 6 DHBsAg and DHBV DNA positive ducks were divided into two groups. In treated group, each duck was injected i.v. AS-ODN 20 micrograms/gram weight/day for 10 dyas successively, while in the control group, each duck received the same volume of normal saline for 10 days. Sera from ducks prior to treatment and treated after 6, 10 days were collected, and after 10 days ducks were sacrificed and livers were examined. DHBsAg was significantly decreased in all three treated ducks after 10 days of AS-ODN treatment. One of these ducks showed decreased DHBsAg even 6 days after treatment. Two out of three treated ducks showed decreased serum DHBV DNA, while one remained unchanged. In contrast, none of the control group showed decreased DHBsAg and DHBV DNA did not change. By Southern blot, DHBV DNA in the liver significantly decreased in 2/3 of the treated ducks and decreased in the other duck. In all control ducks, DHBV DNA remained strongly positive. Data indicated that AS-ODN targeting at Pre-S region could partly inhibit the replication of DHBV.

Animals↗
PubMed1986

Genetic resistance to lethal Sendai virus pneumonia: virus replication and interferon production in C57BL/6J and DBA/2J mice.

Resistant C57BL/6J and susceptible DBA/2J mice were exposed to aerosols of Sendai virus and killed at intervals to 12 days. Lungs were removed and assayed for infectious virus and interferon. Mean virus titers were 6 to 400 times higher in DBA/2J mice than in C57BL/6J mice 3 to 10 days after exposure. Mean interferon titers were 10 to 140 times higher in DBA/2J mice than in C57BL/6J mice 4 to 7 days after exposure. These results suggest that genetic resistance to the lethal effects of Sendai virus is expressed through control of viral replication within the first 72 hours of infection and that early expression of inherited resistance is not regulated by interferon.

Animals↗
PubMed2000

Influence of chronic alcohol abuse on hepatitis C virus replication.

BACKGROUND: Patients with alcoholic liver disease have a high prevalence of hepatitis C virus (HCV) infection. Several workers have shown that HCV-infected alcoholics have more severe biochemical and histological evidence of liver disease than anti-HCV-negative patients. One possible mechanism for the increased liver damage is that alcohol may have a stimulatory effect on HCV replication. The present study was carried out to examine this issue in detail. METHODS: Sixty-eight HCV-infected patients, comprising of 50 chronic alcoholics, consuming 80 g or more of alcohol daily for at least 5 years, and 18 completely abstinent subjects were included in the study. Quantitative HCV-RNA was performed by the branched chain DNA (bDNA) technique. RESULTS: There was no significant difference in the mean serum HCV titers in chronic alcoholics compared to nonalcoholic subjects. Linear regression analysis showed no correlation between the daily ethanol consumption and HCV titers. Seven of the chronic alcoholics, 4 of whom were continuing to drink and 3 who had become abstinent, were retested after 6 months. There was no definite trend in the viral titers, either in abstinent individuals or in those who continued to drink. CONCLUSIONS: These findings suggest that chronic alcohol abuse does not influence the HCV load in the serum. Therefore, the observation that alcoholics with HCV infection have more severe liver damage requires some other explanation than increased HCV viral titers.

Alcoholism↗