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PubMed2004

A NAC domain protein interacts with tomato leaf curl virus replication accessory protein and enhances viral replication.

Geminivirus replication enhancer (REn) proteins dramatically increase the accumulation of viral DNA species by an unknown mechanism. In this study, we present evidence implicating SlNAC1, a new member of the NAC domain protein family from tomato (Solanum lycopersicum), in Tomato leaf curl virus (TLCV) REn function. We isolated SlNAC1 using yeast (Saccharomyces cerevisiae) two-hybrid technology and TLCV REn as bait, and confirmed the interaction between these proteins in vitro. TLCV induces SlNAC1 expression specifically in infected cells, and this upregulation requires REn. In a transient TLCV replication system, overexpression of SlNAC1 resulted in a substantial increase in viral DNA accumulation. SlNAC1 colocalized with REn to the nucleus and activated transcription of a reporter gene in yeast, suggesting that in healthy cells it functions as a transcription factor. Together, these results imply that SlNAC1 plays an important role in the process by which REn enhances TLCV replication.

Amino Acid Sequence↗

PubMed2004

[The contrast study of Pre-S1 protein, HBV-DNA and HBeAg in diagnosing viral replication in patients with chronic hepatitis B].

OBJECTIVE: To determine the role of Pre-S1 protein in diagnosing viral replication in patients with chronic hepatitis B. METHODS: 104 consecutive patients with chronic hepatitis B were included in the study, liver biopsy were performed in all patients. Serial serum samples were studied with the quantitative determination of HBV-DNA by a quantitative PCR assay, determination of Pre-S1 protein by ELISA. RESULTS: The positive rates of HBV-DNA and Pre-S1 protein in patients with HBsAg HBeAg anti-HBc (+) both were 96.5%. The positive rates of HBV-DNA and Pre-S1 protein in patients with HBsAg anti-HBe anti-HBc (+) were 81.5%, 72.3%, respectively. The positive rates of HBV-DNA and Pre-S1 protein in patients with HBsAg anti-HBc (+) were 87.5%, 75.0%, respectively. It represented some patients with HBeAg (-) anti-HBe (+/-) still had viral replication. HBV-DNA>10(3) copy/ml as positive criteria for diagnosing viral replication, the positive rate of HBeAg, Pre-S1 were 31.5% (28/89), 80.9% (72/89) in patients with HBV-DNA>10(3) copy/ml, respectively. The concordance rates of HBeAg, Pre-S1 with HBV-DNA were 40.0% (42/104), 82.0% (85/104), respectively. CONCLUSION: It showed that Pre-S1 was more sensitive than HBeAg in diagnosing viral replication in patients with chronic hepatitis B.

Adult↗

PubMed2001

Inhibitory effects of small-molecule CCR5 antagonists on human immunodeficiency virus type 1 envelope-mediated membrane fusion and viral replication.

We established a human immunodeficiency virus type 1 (HIV-1) envelope (Env)-mediated membrane fusion assay and examined the small-molecule CCR5 antagonist TAK-779 and its derivatives for their inhibitory effects on HIV-1 Env-mediated membrane fusion and viral replication. The membrane fusion assay is based on HIV-1 long terminal repeat-directed beta-D-galactosidase reporter gene expression in CD4- and CCR5-expressed HeLa (MAGI-CCR5) cells after cocultivation with effector 293T cells expressing HIV-1 Env. Inhibition of HIV-1 replication was also determined in MAGI-CCR5 cells infected with the corresponding cell-free HIV-1. TAK-779 effectively suppressed R5 HIV-1 (strain JR-FL) Env-mediated membrane fusion as well as viral replication. Its 50% inhibitory concentrations (IC(50)s) for membrane fusion and viral replication were 0.87 +/- 0.11 and 1.4 +/- 0.1 nM, respectively. These values corresponded well to the IC(50) for (125)I-RANTES (regulated on activation, T cell expressed, and secreted) binding to CCR5 (1.4 nM). The inhibitory effects of 18 TAK-779 derivatives on membrane fusion differed from one compound to another. However, there was a close correlation among their inhibitory effects on membrane fusion, viral replication, and RANTES binding. The correlation coefficient between their IC(50)s for membrane fusion and viral replication was 0.881. Furthermore, since this assay depends on Env expressed in the effector cells, it is also applicable to the evaluation of CXCR4 antagonists. These results indicate that the HIV-1 Env-mediated membrane fusion assay is a useful tool for the evaluation of entry inhibitors.

Amides↗

PubMed2026

Programmed ribosomal frameshifting triggers translational stress to promote viral replication.

Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.

RNA virus↗

PubMed2006

Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication.

Enterovirus 71 is an enterovirus of the family Picornaviridae. The 2C protein of poliovirus, a relative of enterovirus 71, is essential for viral replication. The poliovirus 2C protein is associated with host membrane vesicles, which form viral replication complexes where viral RNA synthesis takes place. We have now identified a host-encoded 2C binding protein called reticulon 3, which we found to be associated with the replication complex through direct interaction with the enterovirus 71-encoded 2C protein. We observed that the N terminus of the 2C protein, which has both RNA- and membrane-binding activity, interacted with reticulon 3. This region of interaction was mapped to its reticulon homology domain, whereas that of 2C was encoded by the 25th amino acid, isoleucine. Reticulon 3 could also interact with the 2C proteins encoded by other enteroviruses, such as poliovirus and coxsackievirus A16, implying that it is a common factor for such viral replication. Reduced production of reticulon 3 by RNA interference markedly reduced the synthesis of enterovirus 71-encoded viral proteins and replicative double-stranded RNA, reducing plaque formation and apoptosis. Furthermore, reintroduction of nondegradable reticulon 3 into these knockdown cells rescued enterovirus 71 infectivity, and viral protein and double-stranded RNA synthesis. Thus, reticulon 3 is an important component of enterovirus 71 replication, through its potential role in modulation of the sequential interactions between enterovirus 71 viral RNA and the replication complex.

Animals↗

PubMed2001

Quantification of intrinsic residual viral replication in treated HIV-infected patients.

The intrinsic rate of viral replication in HIV-infected patients treated with antiretroviral combination therapy is estimated by using a mathematical model of viral dynamics. This intrinsic replication is found to be episodic, varying considerably in quantity between patients (even among those achieving long-term undetectable levels of viremia) and is always reduced by increasing the potency of the antiviral drug regimen. The analysis reveals that even in conditions of perfect patient adherence and drug penetration a substantial level of residual viral replication is expected. The rate of evolution in the viral quasispecies, and thus also the probability of new drug-resistant viral strains being created, is proportional to the total amount of residual viral replication. Under most circumstances, the viral population continues to turn over rapidly during therapy, albeit at a much reduced level.

Anti-HIV Agents↗

PubMed1997

Diminishing adenovirus gene expression and viral replication by promoter replacement.

The adenovirus E4 promoter was replaced by a synthetic promoter composed of a minimal TATA box and five consensus 17-mer yeast GAL4-binding-site elements. The viral vectors, which also contained human factor IX (hFIX) cDNA driven by Rous sarcoma virus long terminal repeat in the E1 region, were then constructed and expanded in 293 cells permanently expressing GAL4/VP16 fusion protein. Viral replication and expression of adenovirus E4 genes and late genes (hexon and fiber) were evaluated in vitro in the human lung carcinoma cell line H1299. Viral replication and viral gene expression were dramatically reduced in the cells transduced by vectors with a replaced E4 promoter compared to the levels in the cells transduced by vectors with the wild-type E4 promoter. The levels of transgene (hFIX) expression remained similar between vectors with or without E4 promoter replacement. These results indicate that diminution of viral gene expression and viral replication is achievable by promoter replacement.

Adenoviridae↗

PubMed2000

Mutations and deletions in core promoter and precore stop codon in relation to viral replication and liver damage in Singaporean hepatitis B virus carriers.

BACKGROUND: The core promoter of hepatitis B virus (HBV) is crucial for the viral replication and mutations may lead to the establishment of chronic infection and development of liver diseases. We analysed this region in Singaporean HBV carriers and assessed their association with viral replication and liver damage. MATERIALS AND METHODS: Thirty-three Singaporean HBV carriers were selected. Serological markers for HBV infection and indicators for liver functions were analysed using commercial kits. Among these patients, 17 were chronic carriers, 10 had cirrhotic livers and 6 others had hepatocellular carcinoma (HCC). The region on the HBV genome covering the entire core promoter and core gene was amplified for each patient by polymerase chain reaction. The amplified DNA fragments were sequenced and analysed. RESULTS: The incidence of mutations in the core promoter or the precore gene product (stop codon at amino acid 28) was not significantly higher compared with the wild type sequences in patients with liver damage. Most mutations in either the core promoter or precore gene significantly reduced the viral replication, as indicated by HBV DNA levels. High levels of HBV DNA were found in three mutants with deletion in the same region, presumably the binding site of liver enriched factor, within the core promoter. CONCLUSION: Our findings revealed a different mutation pattern in the core promoter in Singaporean HBV carriers. While most mutations may not be directly associated with the development of liver diseases, deletions in the core promoter could contribute to enhanced viral replication and should be studied further.

Adult↗

PubMed2005

Bioluminescence imaging of vaccinia virus: effects of interferon on viral replication and spread.

Whole animal imaging allows viral replication and localization to be monitored in intact animals, which provides significant advantages for determining viral and host factors that determine pathogenesis. To investigate effects of interferons on spatial and temporal progression of vaccinia infection, we generated recombinant viruses that express firefly luciferase or a monomeric orange fluorescent protein. These viruses allow vaccinia infection to be monitored with bioluminescence or fluorescence imaging, respectively. The recombinant viruses were not attenuated in vitro or in vivo relative to a control WR virus. In cell culture, reporters could be detected readily by 4 h post-infection, showing that these viruses can be used as early markers of infection. The magnitude of firefly luciferase activity measured with bioluminescence imaging in vitro and in vivo correlated directly with increasing titers of vaccinia virus, validating imaging data as a marker of viral infection. Replication of vaccinia was significantly greater in mice lacking receptors for type I interferons (IFN I R-/-) compared with wild-type mice, although both genotypes of mice developed focal infections in lungs and brain after intranasal inoculation. IFN I R-/- mice had greater dissemination of virus to liver and spleen than wild-type animals even when mortality occurred at the same time point after infection. Protective effects of type I interferons were mediated primarily through parenchymal cells rather than hematopoietic cells as analyzed by bone marrow transplant experiments. Collectively, our data define a new function for type I interferon signaling in systemic dissemination of vaccinia and validate these reporter viruses for studies of pathogenesis.

Animals↗

PubMed1996

Stability in controlling viral replication identifies long-term nonprogressors as a distinct subgroup among human immunodeficiency virus type 1-infected persons.

Long-term nonprogressors (LTNPs) of human immunodeficiency virus type 1 (HIV-1) infection are characterized by low levels of HIV-1 replication and viral load. However, it has not been established whether they differ in this regard from progressors from the very early stage of infection. By studying peripheral blood mononuclear cell (PBMC) specimens from a longitudinally monitored cohort of HIV-1-infected men, we found that HIV-1 proviral copy numbers and HIV-1 mRNA expression levels as low or lower than those seen in seven carefully selected LTNPs were commonly observed in specimens collected soon after seroconversion from 28 subjects who became infected while under observation. However, only the LTNPs were able to stably maintain such an efficient viral control over time. Because of the instability of the early control of HIV-1 replication, the predictive value of HIV-1 mRNA expression in PBMCs at postseroconversion was found to be limited but significantly increased during the first year of infection. Besides their diagnostic implications, these data support the idea that LTNPs may be a pathophysiologically distinct subgroup among persons infected with HIV-1.

Cohort Studies↗

PubMed1989

[Viral replication, histologic damage and enzymatic activity in chronic hepatopathies caused by B virus. Analysis of 21 patients].

In 21 patients from the out-patient clinic of the Internal Medicine Department of our hospital with chronic hepatitis (HC) due to B virus (HBV) and anti-HBC (IgG) serology but not HBsAg, a study was made of the possible correlation between viral replication levels (RV) --as expressed by DNA polymerase values (DNAp)-- and, respectively, histologic changes and serum enzyme movements (GPT, GOT). Our study parted from the diverse criteria cited in the literature concerning the role assigned to viral replication per se and/or immune response per se in the genesis of histologic damage (DH). All patients exhibited signs of moderate clinical and enzymatic activity. The levels of viral replication in the group studies were significant (compared to a control group), which supports the thesis that a certain degree of viral replication, although very attenuated, persists in these patients and is the basis of the continued histological damage that eventually leads to liver cirrhosis (CH) and its derivatives, often with little clinical translation. As regards histologic damage, the correlation with DNAp is reciprocal and of moderate significance, supporting the criterion that the multiform expression of histologic damage in liver cirrhosis due to HBV (HCB) (cellular necrosis, intracellular degenerative phenomena, inflammatory cellular infiltrate, fibrosis) is, at the very least, unproportional to the degree of viral replication and can even be reciprocal. Only the severity of the overall hepatic process remains a function of immune response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2003

Requirement of caspase-3 for efficient apoptosis induction and caspase-7 activation but not viral replication or cell rounding in cells infected with vesicular stomatitis virus.

Infection with vesicular stomatitis virus (VSV), a rhabdovirus and economically significant animal pathogen, was previously demonstrated to induce apoptosis. The mechanism of induction and the role of apoptosis in the VSV-host response have not been completely elucidated. Previous data from our laboratory have suggested that caspase-3 is required for the induction of apoptosis but not viral replication in VSV-infected cells. However, these studies used inhibitors that are selective but not specific for caspase-3. To circumvent this difficulty, we infected both MCF-7 cells which do not express caspases-3 (null), and stable transfectants which express caspase-3 (C3+). When caspase-3 null cells were infected, significant PARP cleavage did not occur, but when C3+ cells were infected, PARP cleavage did occur efficiently. Studies in null and C3+ also suggest that: (1) caspases-3 and -7 are activated sequentially after VSV infection; (2) cell shrinkage and detachment are caspase-3 dependent, but cell rounding is not; and (3) the viral titers were similar between caspase-3 null and C3+ cells suggesting that activation of caspases-3 and -7 are not required for viral replication. Taken together, these results strongly support that the activation of caspase-3 by VSV infection is required for efficient apoptosis induction but not viral replication in vitro. Apoptosis mediated by caspase-3, then, is likely either a host cell response to viral replication or perhaps may be required for in vivo viral replication and spread.

Apoptosis↗

PubMed2004

The impact of early immune destruction on the kinetics of postacute viral replication in rhesus monkey infected with the simian-human immunodeficiency virus 89.6P.

Set-point viral load is positively correlated with the extent of initial viral replication in pathogenic simian-human immunodeficiency virus (SHIV) infection. To elucidate the mechanisms underlying the correlation, we conducted a systematic investigation in rhesus monkeys infected with the highly pathogenic SHIV 89.6P. This model is widely used in the preclinical evaluation of AIDS vaccine candidates and a thorough understanding of the model's biology is important to the proper interpretation of these evaluations. We found that the levels of peak viremia were positively correlated not only with the levels of set-point viremia but, importantly, with the extent of initial overall immune destruction as indicated by the degree of CD4+ T cell depletion and lymph node germinal center (GC) formation. The extent of initial overall immune destruction was inversely correlated with subsequent development and maintenance of virus-specific cellular and humoral immune responses. Thus, these data suggest that the extent of early immune damage determines the development and durability of virus-specific immunity, thereby playing a critical role in establishing the levels of set-point viral replication in SHIV infection. Vaccines that limit both the initial viral replication and the extent of early immune damage will therefore mediate long-term virus replication control and mitigation of long-term immune destruction in this model of immunodeficiency virus infection.

Acute Disease↗

PubMed2000

High levels of viral replication during primary simian immunodeficiency virus SIVagm infection are rapidly and strongly controlled in African green monkeys.

In contrast to pathogenic human immunodeficiency virus and simian immunodeficiency virus (SIV) infections, chronic SIVagm infections in African green monkeys (AGMs) are characterized by persistently low peripheral and tissue viral loads that correlate with the lack of disease observed in these animals. We report here data on the dynamics of acute SIVagm infection in AGMs that exhibit remarkable similarities with viral replication patterns observed in peripheral blood during the first 2 weeks of pathogenic SIVmac infections. Plasma viremia was evident at day 3 postinfection (p.i.) in AGMs, and rapid viral replication led by days 7 to 10 to peak viremias characterized by high levels of antigenemia (1.2 to 5 ng of p27/ml of plasma), peripheral DNA viral load (10(4) to 10(5) DNA copies/10(6) peripheral blood mononuclear cells [PBMC]), and plasma RNA viral load (2 x 10(6) to 2 x 10(8) RNA copies/ml). The lymph node (LN) RNA and DNA viral load patterns were similar to those in blood, with peaks observed between day 7 and day 14. These values in LNs (ranging from 3 x 10(5) to 3 x 10(6) RNA copies/10(6) LN cell [LNC] and 10(3) to 10(4) DNA copies/10(6) LNC) were at no time point higher than those observed in the blood. Both in LNs and in blood, rapid and significant decreases were observed in all infected animals after this peak of viral replication. Within 3 to 4 weeks p. i., antigenemia was no longer detectable and peripheral viral loads decreased to values similar to those characteristic of the chronic phase of infection (10(2) to 10(3) DNA copies/10(6) PBMC and 2 x 10(3) to 2 x 10(5) RNA copies/ml of plasma). In LNs, viral loads declined to 5 x 10(1) to 10(3) DNA copies and 10(4) to 3 x 10(5) RNA copies per 10(6) LNC at day 28 p.i. and continued to decrease until day 84 p.i. (<10 to 3 x 10(4) RNA copies/10(6) LNC). Despite extensive viremia during primary infection, neither follicular hyperplasia nor CD8(+) cell infiltration into LN germinal centers was detected. Altogether, these results indicate that the nonpathogenic outcome of SIVagm infection in its natural host is associated with a rapidly induced control of viral replication in response to SIVagm infection, rather than with a poorly replicating virus or a constitutive host genetic resistance to virus replication.

Animals↗

PubMed2000

Residual low-level viral replication could explain discrepancies between viral load and CD4+ cell response in human immunodeficiency virus-infected patients receiving antiretroviral therapy.

We report the evolution of chronic infection with human immunodeficiency virus type 1 (HIV-1) in a patient treated with stavudine plus didanosine, whose CD4+ lymphocyte count progressively decreased, despite a sustained plasma viral load <20 copies/mL. After 12 months of therapy, treatment was switched to zidovudine plus lamivudine plus nelfinavir. CD4+ T cell count decreased from 559 x 10(6)/L at month 0 to 259 x 10(6)/L at month 12. Plasma viral load decreased from 21,665 HIV-1 RNA copies/mL at baseline (month 0) to <20 copies/mL after 1 month of therapy with stavudine plus didanosine, and remained below 20 copies/mL until month 12, but always >5 copies/mL. Viral load in tonsilar tissue at month 12 was 125,000 copies/mg of tissue. After the change to triple-drug therapy, the plasma viral load decreased to 5 copies/mL, the CD4+ T cell count increased to 705 x 10(6)/L, and the viral load in tonsilar tissue decreased to <40 copies/mg of tissue at month 24. A low level of HIV-1 replication could explain the lack of immunologic response in patients with apparent virological response.

Adenoids↗

PubMed1986

Chronic hepatitis B virus infection. Viral replication and patterns of inflammatory activity: serological, clinical and histological correlations.

We have studied serum and tissue markers of viral replication in 39 patients with chronic hepatitis B virus (HBV) infection and correlated these with periportal and lobular activity in liver biopsies. HBV DNA positivity correlated with the presence of hepatitis B e antigen (HBeAg, P less than 0.001) and aspartate transaminase (AST) levels (P less than 0.005). The lobular but not the periportal inflammatory activity was significantly associated with the presence of HBV DNA (P less than 0.02) and HBeAg (P less than 0.001) and with higher AST levels. The periportal activity correlated with the periportal and lobular display of beta 2-microglobulin on hepatocytes (P less than 0.001 and P less than 0.002, respectively). In patients with chronic HBV infection therefore, the lobular rather than the periportal component of activity was related to viral replication. The association of display of beta 2-microglobulin on hepatocytes with the inflammatory process, in patients with active viral replication, is consistent with the hypothesis that increased display of HLA type I enhances recognition of hepatocytes bearing viral proteins and allows lysis of immune cells.

Adult↗

PubMed1997

The degrees of hepatocyte nuclear but not cytoplasmic expression of hepatitis B core antigen reflect the level of viral replication in chronic hepatitis B virus infection.

Although immunodetection of hepatitis B core antigen (HBcAg) in the liver has long been recognized as a marker of active hepatitis B virus (HBV) replication, the correlation between the level of viral replication and the degrees of expression of HBcAg in hepatocytes remains to be established. In this study, we examined the semiquantitative relationship between the level of HBV DNA in serum and the degree of expression of HBcAg in the hepatocyte nucleus or cytoplasm in 80 adults with chronic hepatitis B. Expression of HBcAg in hepatocytes was studied by the avidin-biotin immunoperoxidase method, and the results were scored on a scale of 0 to 4, values corresponding to the positivity of 0, 1 to 10, 11 to 25, 26 to 50, and > 50%, respectively, of hepatocytes examined. Serum HBV DNA was tested by a liquid hybridization assay, and the results were scored on a scale of 0 to 5, values corresponding to undetectable levels and levels of < or = 50, 51 to 100, 101 to 150, 151 to 200, and > 200 pg/ml, respectively. The results revealed a highly significant, positive correlation between the level of HBV DNA in serum and the degree of expression of HBcAg in nuclei (Spearman rank correlation coefficient [rs] = 0.653, P < 0.001). The mean scores (95% confidence intervals) of levels of HBV DNA in sera of patients whose levels of expression of HBcAg in nuclei received a score of 0 (n = 33), 1 or 2 (n = 35), and 3 or 4 (n = 12) were 1.3 (1.1 to 1.5), 2.5 (2.1 to 2.9), and 3.9 (3.1 to 4.7), respectively. However, no correlation between the level of HBV DNA in serum and the degree of expression of HBcAg in the cytoplasm was noted (rs = 0.026, P > 0.8). In conclusion, the degree of expression of HBcAg in the hepatocyte nucleus but not the cytoplasm can accurately reflect the level of viral replication in patients with chronic hepatitis B.

Adult↗

PubMed1983

Lethal infection with murine cytomegalovirus after early viral replication in the spleen.

In acute lethal murine cytomegalovirus (MCMV) infection the spleen and liver are the principal sites of early viral replication. MCMV titers increase rapidly in the spleen and liver, exceeding 10(6) and 10(5) plaque-forming units (pfu)/g of tissue, respectively, within 96 hr of viral inoculation. Experiments were performed to determine the impact of early splenic viral replication on disease pathogenesis. Splenectomized mice survived acute infection in significantly greater numbers (25 of 34 vs 14 of 33, respectively) than controls and had lower hepatic viral titers (1.9 X 10(4) vs 2.4 X 10(5) pfu/g, respectively). Examination of the spleen by electron microscopy after administration of phagocytic markers demonstrated that macrophages were the predominant site of viral replication. It is concluded that early replication of MCMV in splenic macrophages augments virus-induced hepatic injury and thus contributes to the pathogenesis of lethal MCMV infection.

Animals↗