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PubMed1999

Lamivudine. A review of its therapeutic potential in chronic hepatitis B.

UNLABELLED: Lamivudine is a deoxycytidine analogue that is active against hepatitis B virus (HBV). In patients with chronic hepatitis B, lamivudine profoundly suppresses HBV replication. Clinically significant improvements in liver histology and biochemical parameters were obtained with lamivudine in double-blind, randomised, trials in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B and compensated liver disease. After 52 weeks of treatment, relative to placebo (< or = 25%), significantly more Chinese (56%) or Western patients (52%) treated with lamivudine 100 mg/day had reductions of > or = 2 or more points in Knodell necro-inflammatory scores. Moreover, significantly fewer lamivudine 100 mg/day than placebo recipients had progressive fibrosis in liver biopsies (< or = 5 vs > or = 15%) and fewer lamivudine- than placebo-treated patients progressed to cirrhosis (1.8 vs 7.1%). More lamivudine 100 mg/day than placebo recipients acquired antibodies to HBeAg after 52 weeks (16 vs 4% in Chinese patients and 17 vs 6% in Western patients). ALT levels normalised in significantly more lamivudine than placebo recipients enrolled in these trials. In HBeAg-negative, HBV DNA positive patients with compensated liver disease enrolled in a double-blind, randomised study, HBV DNA levels were suppressed to below the limit of detection (< 2.5 pg/ml) and ALT levels normalised in 63% and 6% of patients treated with lamivudine 100 mg/day or placebo for 24 weeks. Clinically significant improvements in liver histology were obtained in 60% of patients treated with lamivudine for 52 weeks in this study. Lamivudine 100 mg/day for 52 weeks produced similar or significantly greater improvements in liver histology and ALT levels than 24 weeks' treatment with lamivudine plus interferon-alpha. In liver transplant candidates with chronic hepatitis B and end-stage liver disease, lamivudine 100 mg/day alone, or in combination with hepatitis B immune globulin, generally suppressed HBV replication and appeared to protect the grafted liver from reinfection. Lamivudine 100 mg/day suppressed viral replication and improved liver histology in liver transplant recipients with recurrent or de novo chronic hepatitis B. Lamivudine 300 or 600 mg/day reduced HBV replication in HIV-positive patients. The incidence of adverse events in patients with chronic hepatitis B and compensated liver disease treated with lamivudine 100 mg/day or placebo for 52 to 68 weeks was similar. 3.1- to 10-fold increases in ALT over baseline occurred in 13% of patients during treatment with lamivudine 100 mg/day or placebo for 52 weeks. Post-treatment ALT elevations were more common in lamivudine than placebo recipients; however, these generally resolved spontaneously; < or = 1.5% of lamivudine- or placebo-treated patients experienced hepatic decompensation. CONCLUSION: Lamivudine inhibits HBV replication, reduces hepatic necro-inflammatory activity and the progression of fibrosis in patients with chronic hepatitis B, ongoing viral replication and compensated liver disease including HBeAg-negative patients. The drug also suppresses viral replication in liver transplant recipients and HIV-positive patients. Thus, lamivudine is potentially useful in a wide range of patients with chronic hepatitis B and ongoing viral replication.

Animals↗
PubMed1989

Several rat cell lines share a common defect in their inability to internalize murine coronaviruses efficiently.

Infection of rat cells, Schwannoma RN2, hepatoma HTC or myoblast L6, with the murine coronavirus JHM strain results in a persistent infection characterized by the release of virus over an extended period of time with a limited cytopathology. Several stages of the viral replication cycle have been examined in these cells in comparison to those in mouse L2 cells, which are totally permissive to JHM infection. Although the rat cells bound as much virus as the mouse cells. Their ability to internalize it was 40-fold less efficient than the mouse cells. This lower internalization efficiency was not enhanced by pH shock of infected cells, but was by treatment with polyethylene glycol. In all cell types there appeared to be no major differences in the ability of the internalized virus to replicate the viral RNA as determined by slot-blot analysis with a radiolabelled viral cDNA. A similar genetic mechanism appears to be operative in the lines because somatic cell hybrids formed between these lines in various combinations were also deficient in the ability to internalize bound virus. Taken together these results imply that rat cell lines in general share a common deficiency in their inability to internalize murine coronaviruses efficiently. This low efficiency in viral internalization may explain in part the ability of these lines to sustain persistent infections.

Adhesiveness↗
PubMed1996

Modification of viral myocarditis in mice by interleukin-6.

Inflammatory cytokines play a key role in the myocardial injury produced by viral myocarditis. Although interleukin-6 (IL-6) reportedly possesses antiviral properties, its effect in viral myocarditis is unclear. To investigate the role of IL-6 in viral myocarditis induced by encephalomyocarditis virus (EMCV) in mice, we evaluated (1) the survival rate following IL-6 administration, (2) the viral titer in the heart, (3) viral replication in the heart by in situ hybridization, (4) histopathological changes using immunohistochemical staining, (5) neutralizing antibody against EMCV, (6) circulating interferon and tumor necrosis factor-alpha (TNF-alpha), (7) viral suppression in vitro by IL-6, and (8) natural killer (NK)-cell activity. Eight-week-old C3H/HeJ mice were injected intraperitoneally with EMCV (day 0) and were also injected subcutaneously twice daily for 4 consecutive days with 10 micrograms/0.1 mL of human IL-6 on day -4 (group A), day 0 (group B), or day +4 (group D) for 4 days. As a control, 0.1 mL PBS instead of IL-6 was injected on day 0 for 4 days (group C). Certain mice were killed on day 4. The myocardial virus titers, viral replication in situ, and NK-cell activity in the spleen were determined. Decreased viral titer and viral replication in the heart reduced the titer of circulating TNF-alpha, and lower NK-cell activity was observed in group B versus group C (control group). The titer of neutralizing antibodies against EMCV was significantly (P < .05) increased in group B compared with group C. The remaining mice were killed on days 10 and 30 after infection. The ratio of heart weight (HW) to body weight (BW) and myocardial injury in group B were reduced versus group C on days 10 and 30. The HW of group B on day 30 did not differ from the normal control group. The ratio of splenic weight to BW and the ratio of thymic weight to BW of group B increased on day 10, with expanded follicles observed in the spleen and enlargement of the medulla observed in the thymus. Immunohistochemical study revealed an increased percentage of macrophages in the heart and spleen of group B. In summary, IL-6 reduces myocardial damage in mice with viral myocarditis. Modification of immune responses together with reduction in viral replication appears to be the mechanism of the IL-6 effect. Although IL-6 is likely important in the process of viral antigen presentation, early activation of immune responses and attenuation of viral replication appear most significant, as reflected in the limited time window during which IL-6 is effective in myocarditis.

Animals↗
PubMed1995

Release of the catalytic domain N(o) from the herpes simplex virus type 1 protease is required for viral growth.

The herpes simplex virus type 1 (HSV-1) protease and its substrate, ICP35, are involved in the assembly of viral capsids and required for efficient viral growth. The full-length protease (Pra) consists of 635 amino acid (aa) residues and is autoproteolytically processed at the release (R) site and the maturation (M) site, releasing the catalytic domain No (VP24), Nb (VP21), and a 25-aa peptide. To understand the biological importance of cleavage at these sites, we constructed several mutations in the cloned protease gene. Transfection assays were performed to determine the functional properties of these mutant proteins by their abilities to complement the growth of the protease deletion mutant m100. Our results indicate that (i) expression of full-length protease is not required for viral replication, since a 514-aa protease molecule lacking the M site could support viral growth; and that (ii) elimination of the R site by changing the residue Ala-247 to Ser abolished viral replication. To better understand the functions that are mediated by proteolytic processing at the R site of the protease, we engineered an HSV-1 recombinant virus containing a mutation at this site. Analysis of the mutant A247S virus demonstrated that (i) the mutant protease retained the ability to cleave at the M site and to trans process ICP35 but failed to support viral growth on Vero cells, demonstrating that release of the catalytic domain No from Pra is required for viral replication; and that (ii) only empty capsid structures were observed by electron microscopy in thin sections of A247S-infected Vero cells, indicating that viral DNA was not encapsidated. Our results demonstrate that processing of ICP35 is not sufficient to support viral replication and provide genetic evidence that the HSV-1 protease has nuclear functions other than enzymatic activity.

Amino Acid Sequence↗
PubMed1988

Cytomegalovirus infection and viral-induced transformation of human endothelial cells.

Human cytomegalovirus (CMV) has been associated with vascular pathology. In vivo, CMV is present in vessel wall cells during acute and chronic infections as well as in atherosclerotic lesions. CMV nucleic acids and proteins have also been detected within Kaposi's sarcoma lesions. Because of these associations, we studied the interaction of CMV with human endothelial cells with particular attention to its oncogenicity in this cell type. Our data demonstrate that human endothelial cells are permissive to viral replication but that the viral replication cycle is delayed compared with fibroblast cells. Persistent infections can result with minimal cytopathology. CMV can transform these cells to anchorage-independent growth, and noninfectious virus is still capable of inducing this transforming event. Our results demonstrate that productive or persistent CMV infection of endothelial cells and viral-induced transformation can occur, thus providing an in vitro correlate of in vivo events.

Antibodies, Viral↗
PubMed1997

Cucumber mosaic virus is restricted from entering minor veins in transgenic tobacco exhibiting replicase-mediated resistance.

Transgenic tobacco plants expressing an altered form of the 2a replicase gene from cucumber mosaic virus (CMV) strain Fny exhibited a suppression of viral replication and restricted viral movement when inoculated mechanically or by insect vectors. Resistant plants could be infected, however, through a graft-union with an infected nontransformed plant. The infectious entity moved quickly through intergrafts of resistant tissue, indicating that it could move without replicating in the vascular system. Viral replication continued to be suppressed in systemically infected transgenic portions of grafted plants, as demonstrated by the synthesis of lower levels of viral RNA than in systemically infected nontransformed portions of the same grafted plants. Cell-to-cell spread within this tissue also occurred much more slowly than in nontransformed tobacco. Young inoculated levels of transgenic-resistant plants exhibited limited cell-to-cell virus movement, revealed as chlorotic lesions, but no long-distance virus movement occurred. The results of in situ hybridization studies on these lesions indicated that CMV RNA does not traffic from bundle-sheath cells to vascular parenchyma or companion cells in chlorotic lesions on the inoculated leaves of transgenic-resistant tobacco plants. The inhibition of long-distance movement was a consequence of restricted entry of the infectious entity into the vascular system.

Cucumovirus↗
PubMed1990

Extracts of hamster cells abortively infected with human adenovirus type 12 are competent to support initiation of viral DNA replication.

Baby hamster kidney (BHK-21) cells do not allow replication of human adenovirus type 12 (Ad12) DNA during abortive infection by this virus. However, we have determined that crude extracts of BHK-21 cells abortively infected with Ad12 support in vitro the initiation reaction of Ad12 DNA replication. Synthesis of the Ad12 pTP-dCMP initiation complex by BHK extracts is two- to five-fold less than when crude infected human (KB) cell extracts are used in the reaction. Combining infected KB cytoplasmic and uninfected BHK nuclear extracts in the reaction indicates that the decreased efficiency is probably due to a lesser ability of hamster nuclear extracts to support the initiation reaction, rather than to decreased synthesis of Ad12 pTP and DNA polymerase during abortive infection, or to the presence of an inhibitor in BHK cells.

Adenoviridae↗
PubMed1991

Control of adenovirus alternative RNA splicing: effect of viral DNA replication on RNA splice site choice.

The primary transcripts of most adenovirus transcription units are processed into multiple, alternatively spliced mRNAs. The relative concentrations of such differentially processed mRNAs changes during the infectious cycle. The factors that control this temporal shift in mRNA abundance have not yet been characterized. In the experiments presented here we have examined mRNA synthesis from three viral transcription units: two early regions E1a and E1b, and late region L1. We show that viral DNA replication plays a key role in the control of cytoplasmic mRNA expression from these regions. In the absence of efficient late protein synthesis, viral DNA replication was sufficient to induce a substantial fraction of the E1a, E1b and L1 transcripts to shift from the early to the late pattern of mRNA structure. The shift was not complete under the conditions used, suggesting that viral proteins, although not essential for the process, play an important regulatory role. The requirement for late viral protein synthesis differed between the three transcription units examined. This dependence was most pronounced for correct L1 mRNA production. Viral DNA replication was sufficient to trigger a significant shift in L1 alternative 3' splice site selection. However, in the absence of late translation the L1 pre-mRNA was aberrantly spliced.

Adenovirus Early Proteins↗
PubMed2003

IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication.

Th1-type immune responses, mediated by IL-12-induced IFN-gamma, protect the host from most viral infections. To investigate the role of IL-12 and IFN-gamma on the development of Coxsackievirus B3 (CB3)-induced myocarditis, we examined the level of inflammation, viral replication, and cytokine production in IL-12Rbeta1- and IFN-gamma-deficient mice following CB3 infection. We report that IL-12Rbeta1 deficiency results in decreased viral replication and inflammation in the heart, while IFN-gamma deficiency exacerbates CB3 replication. Importantly, decreased IL-1beta and IL-18 levels in IL-12Rbeta1-deficient hearts correlated directly with decreased myocardial inflammation. Because IL-1beta and IL-18 were associated with myocardial inflammation, we examined the effect of TLR4 deficiency on CB3 infection and myocarditis. We found that TLR4-deficient mice also had significantly reduced levels of myocarditis, viral replication, and IL-1beta/IL-18, just as we had observed in IL-12Rbeta1-deficient mice. This is the first report that TLR4 influences CB3 replication. These results show that IL-12Rbeta1 and TLR4 exacerbate CB3 infection and myocarditis while IFN-gamma protects against viral replication. The remarkable similarities between the effects of IL-12Rbeta1 and TLR4 suggest that these receptors share common downstream pathways that directly influence IL-1beta and IL-18 production, and confirm that IL-1beta and IL-18 play a significant role in the pathogenesis of CB3-induced myocarditis. These findings have important implications not only for the pathogenesis of myocarditis, but for other autoimmune diseases triggered by viral infections.

Acute Disease↗
PubMed2006

Inducible virus-mediated expression of a foreign protein in suspension-cultured plant cells.

Although suspension-cultured plant cells have many potential merits as sources of useful proteins, the lack of an efficient expression system has prevented using this approach. In this study, we established an inducible tomato mosaic virus (ToMV) infection system in tobacco BY-2 suspension-cultured cells to inducibly and efficiently produce a foreign protein. In this system, a modified ToMV encoding a foreign protein as replacement of the coat protein is expressed from stably transformed cDNA under the control of an estrogen-inducible promoter in transgenic BY-2 cells. Estrogen added to the culture activates an estrogen-inducible transactivator expressed constitutively from the transgene and induces transcription and replication of viral RNA. In our experiments, accumulation of viral RNA and expression of green fluorescent protein (GFP) encoded in the virus were observed within 24 h after induction. The amount of GFP reached approximately 10% of total soluble protein 4 d after induction. In contrast, neither viral RNA nor GFP were detected in uninduced cells. The inducible virus infection system established here should be utilized not only for the expression of foreign proteins, but also for investigations into the viral replication process in cultured plant cells.

Capsid Proteins↗
PubMed2003

Trans-complementation of autonomously replicating Bovine viral diarrhea virus replicons with deletions in the E2 coding region.

Autonomously replicating Bovine viral diarrhea virus (BVDV) genomes (replicons) were constructed from the full-length BVDV cDNA clone pA/BVDV/Ins- (G. Meyers et al., J. Virol. 70, 8606-8613, 1996). The sequences coding for envelope protein E2, for E2 without the C-terminal transmembrane region, or for E2 and nonstructural protein p7 were deleted, and the resulting mutants were tested for their ability to replicate after transfection. All deletion mutants were able to replicate and to express the inserted green fluorescent protein but did not produce infectious progeny virus in bovine kidney PT cells. The replicons were also tested for their ability to be trans-complemented in the bovine cell line PT_805, which constitutively expresses BVDV structural proteins. E2-negative BVDV mutants were complemented and >10(6) infectious units were obtained at 24 h after transfection. Complementing PT_805 cells could only inefficiently be infected using trans-complemented virions, however, and low levels of virus production were observed when complemented BVDV was passaged using PT_805 cells. Similarly, infection of PT_805 cells with BVDV was highly inefficient, but transfection of full-length BVDV NCP7 RNA into PT_805 resulted in 10,000-fold higher virus titers when compared to those obtained 24 h after transfection of parental PT cells. We concluded that self-replicating E2-deleted BVDV RNAs can be efficiently trans-complemented by constitutively expressed E2, and that expression of BVDV structural proteins markedly influences susceptibility of cells to BVDV infection as well as BVDV titers after transfection of full-length BVDV RNA.

Animals↗
PubMed2005

Endothelial cells promote human immunodeficiency virus replication in nondividing memory T cells via Nef-, Vpr-, and T-cell receptor-dependent activation of NFAT.

Human endothelial cells (ECs) enhance human immunodeficiency virus (HIV) replication within CD4(+) memory T cells by 50,000-fold in a Nef-dependent manner. Here, we report that EC-mediated HIV type 1 replication is also dependent on an intact vpr gene. Moreover, we demonstrate that despite a requirement for engaging major histocompatibility complex (MHC) class II molecules and costimulators, EC-stimulated virus-producing cells (p24(high) T cells) do not proliferate, nor are they arrested in the cell cycle. Rather, they are minimally activated, sometimes expressing CD69 but not CD25, HLA-DR, VLA-1, or effector cytokines. Blocking antibodies to interleukin 2 (IL-2), IL-6, IL-7, or tumor necrosis factor do not inhibit viral replication. Cyclosporine effectively inhibits viral replication, as does disruption of the NFAT binding site in the viral long terminal repeat. Furthermore, in the presence of ECs, suboptimal T-cell receptor (TCR) stimulation with phytohemagglutinin L supports efficient viral replication, and suboptimal stimulation with toxic shock syndrome toxin 1 leads to viral replication selectively in the TCR-stimulated, Vbeta2-expressing T cells. Collectively, these data indicate that ECs provide signals that promote Nef- and Vpr-dependent HIV replication in memory T cells that have been minimally activated through their TCRs. Our studies suggest a mechanism for HIV replication in vivo within the reservoir of circulating memory CD4(+) T cells that persist despite antiretroviral therapy and further suggest that maintenance of immunological memory by MHC class II-expressing ECs via TCR signaling may contribute to HIV rebound following cessation of antiretroviral therapy.

Antigens, CD↗
PubMed2004

Development of anti-retroviral resistance of HIV-1 infected individuals on therapy: is it inevitable?

Highly active antiretroviral therapy directed against HIV-1 has dramatically modified morbidity and mortality in infected individuals. Enthusiasm for the success of these medications have been tempered by an inability to clear virus from the infected host leaving a virus poised to leverage any advantage into one of productive survival. One mechanism used to accomplish escape from suppression secondary to antiretroviral therapy is by developing mutations. The goal of therapy has been to diminish viral replication, thereby effectively abrogating the development of these resistance-bearing mutations. This strategy has met with significant success but numerous host-viral factors impact on the ability of the clinician to persistently suppress viral load, thereby providing a window of opportunity for the virus to mutate. In particular we review evidence for ongoing viral replication in the face of suppressive antiretroviral therapy and viral replication in tissue compartments. We discuss whether viral resistance can develop during transient elevations in viral load (viral blips) or as a function of the rate of viral load decay while on therapy. Finally, we touch on the therapeutic strategy that diminished viral replication capacity of mutational species can maintain host immunity.

Anti-HIV Agents↗
PubMed2006

Trichosanthin suppresses the elevation of p38 MAPK, and Bcl-2 induced by HSV-1 infection in Vero cells.

Trichosanthin (TCS) is a type 1 ribosome-inactivating protein (RIP) effective against HIV-1 and HSV-1 replication. The mechanism of its antiviral activity is not clear. Many believe that it is related to ribosome inactivation. Some RIPs and viral infection affect the phosphorylation of MAPK and Bcl-2 and these proteins may be the common element linking RIP and viral infection. This study investigated the effect of HSV-1 infection on p38 MAPK and Bcl-2 as well as possible interference by TCS. Results showed that HSV-1 infection induced an elevation of phosphorylated p38 and Bcl-2 in Vero cells, which could be partially blocked by TCS. At the same time, both viral replication and host cells viability were lowered. Viral replication, Vero cell viability, p38 MAPK and Bcl-2 were further reduced with the addition of a p38 MAPK inhibitor (SB203580). This suggested that TCS may interfere with MAPK and Bcl-2 signals generated by infection leading to inhibition of viral replication. In summary, our results demonstrated that HSV-1 infection in Vero cells induced an elevation of p38 MAPK and Bcl-2. TCS suppressed this rise and reduced viral replication. The MAPK family may play a role in the antiviral mechanism of TCS.

Animals↗
PubMed2004

Looking back at smallpox.

Smallpox apparently arose through transfer of variola virus to humans from another animal species. By causing a brief infection that required close contact for transmission and engendered solid immunity, the agent was always vulnerable to simple isolation measures. The high replicative fidelity of the viral DNA polymerase limited variola's ability to adapt to humans and preserved orthopoxviral antigenic cross-reactivity, so that vaccinia vaccination protected against smallpox. Host-derived genes encoding immunomodulatory proteins helped shelter viral replication from innate immune responses. Examination of clinical variants suggests that severity of illness was usually determined by host responses during the incubation period. Control of viral replication was aided by early postexposure vaccination and might be strengthened by additional immunological interventions. Massive inflammatory responses were responsible for major features of illness. Some patients with high levels of circulating virus developed hemorrhagic disease resembling septic shock. Continued study of virus-host interactions is needed to defend against genetically modified agents.

Bioterrorism↗