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PubMed2002

HIV-1 replication cycle.

The HIV-1 is a formidable pathogen with establishment of a persistent infection based on the ability to integrate the proviral genome into chronically infected cells, and by the rapid evolution made possible by a high mutation rate and frequent recombination during the viral replication. HIV-1 has a variety of novel genes that facilitate viral persistence and regulation of HIV replication, but this virus also usurps cellular machinery for HIV replication, particularly during gene expression and virion assembly and budding. Recent success with antiretroviral therapy may be limited by the emergence HIV drug resistance and by toxicities and other requirements for successful long-term therapy. Further investigation of HIV-1 replication may allow identification of novel targets of antiretroviral therapy that may allow continued virus suppression in patients of failing current regiments, particularly drugs that target HIV-1 entry and HIV-1 integration.

Animals↗
PubMed1996

Human rhinovirus 3 at 3.0 A resolution.

BACKGROUND: The over 100 serotypes of human rhinoviruses (HRV) are major causative agents of the common cold in humans. These HRVs can be roughly divided into a major and minor group according to their cellular receptors. They can also be divided into two antiviral groups, A and B, based on their sensitivity to different capsid-binding antiviral compounds. The crystal structures of HRV14 and HRV16, major-receptor group rhinoviruses, as well as HRV1A, a minor-receptor group rhinovirus, were determined previously. Sequence comparisons had shown that HRV14 seemed to be an outlier among rhinoviruses. Furthermore, HRV14 was the only virus with no cellular 'pocket factor' in a hydrophobic pocket which is targeted by many capsid-binding antiviral compounds and is thought to regulate viral stability. HRV3, another major-receptor group virus, was chosen for study because it is one of a subset of serotypes that best represents the drug sensitivity of most rhinovirus serotypes. Both HRV3 and HRV14 belong to antiviral group A, while HRV16 and HRV1A belong to antiviral group B. RESULTS: HRV3 was found to be very similar to HRV14 in sequence and structure. Like HRV14, crystallized HRV3 also has no bound pocket factor. The structure of HRV3 complexed with an antiviral compound, WIN56291, was also determined and found to be similar to the same antiviral compound complexed with HRV14. CONCLUSIONS: The amino-acid sequence and structural similarity between HRV3 and HRV14 suggests that rhinoviruses in the same antiviral group have similar amino-acid sequences and structures. The similar amino-acid composition in the pocket region and the viral protein VP1 N termini in all known group B HRV sequences suggests that these viruses may all contain pocket factors and ordered N-terminal amphipathic helices in VP1. Both of these factors contribute to viral stability, which is consistent with the observations that group B rhinoviruses have a higher chance of successful transmission from one host to another and is a possible explanation for the observed higher pathogenicity of these rhinoviruses.

Antigens, Viral↗
PubMed2026

Reducing haystacks to needles - ViralClust: A Nextflow pipeline to cluster viral sequences.

BACKGROUND: The rapid accumulation of viral genome sequences presents major challenges for downstream analysis tools, including tools for multiple sequence alignments, phylogeny, and genome/alignment visualization, due to computational constraints and sampling biases caused by outbreak-driven over-representation. Selecting representative genomes through clustering offers a principled alternative to random subsampling, yet choosing appropriate clustering strategies remains non-trivial and context-dependent. RESULTS: Here, we present ViralClust, a modular Nextflow pipeline for bias-aware representative selection from large viral genome datasets. ViralClust integrates five distinct clustering algorithms (CD-HIT-EST, SUMACLUST, VSEARCH, MMSeqs2, and HDBSCAN) within a unified workflow, enabling direct comparison of clustering outcomes and flexible adaptation to diverse biological questions, considering a balanced phylogenetic distribution of the selected sequences. We evaluated ViralClust on six RNA and DNA virus datasets ranging from 632 to 156,586 sequences and spanning genome lengths from 890 to 197,185 nucleotides. Across all datasets, clustering reduced dataset size by ~95 % or more while preserving genetic diversity across species, genera, and families, and effectively mitigating biases introduced by outbreaks, partial genomes, and sequence orientation artifacts. CONCLUSIONS: By supporting whole-genome clustering and scalable representative selection, ViralClust enables efficient and reproducible downstream analyses that would otherwise be computationally infeasible. Rather than offering a prescriptive, guided analysis engine, our framework functions as a flexible comparative collection of complementary strategies, allowing users to empirically evaluate trade-offs and choose the ideal method tailored to their specific analytical endpoints.

Bioinformatics↗
PubMed2004

Host RNA polymerase II makes minimal contributions to retroviral frame-shift mutations.

The rate of mutation during retrovirus replication is high. Mutations can occur during transcription of the viral genomic RNA from the integrated provirus or during reverse transcription from viral RNA to form viral DNA or during replication of the proviral DNA as the host cell is dividing. Therefore, three polymerases may all contribute to retroviral evolution: host RNA polymerase II, viral reverse transcriptases and host DNA polymerases, respectively. Since the rate of mutation for host DNA polymerase is very low, mutations are more likely to be caused by the host RNA polymerase II and/or the viral reverse transcriptase. A system was established to detect the frequency of frame-shift mutations caused by cellular RNA polymerase II, as well as the rate of retroviral mutation during a single cycle of replication in vivo. In this study, it was determined that RNA polymerase II contributes less than 3 % to frame-shift mutations that occur during retrovirus replication. Therefore, the majority of frame-shift mutations detected within the viral genome are the result of errors during reverse transcription.

Animals↗
PubMed1990

Sequence analysis of gene 11 equivalents from "short" and "super short" strains of rotavirus.

The molecular basis for the aberrant migration pattern of the gene 11 equivalent in rotaviruses with "short" (human DS-1) and "super short" (human 69M and bovine VMRI) electropherotypes was investigated. The mRNAs of these viruses were synthesized in vitro, and the entire gene 11 equivalent of each of these viruses was sequenced with specific synthetic oligonucleotide primers. These sequences were compared with previously published sequences of "long" pattern rotavirus gene 11 segments. The increased lengths of the gene 11 equivalents of DS-1, 69M, and VMRI are due to a prolonged, 3' untranslated region in this gene segment. The 3' untranslated region of the VMRI gene 11 equivalent contains a clear duplication of a portion of its coding sequence. A stretch of 18 consecutive nucleotides within the 330-nucleotide, 3' untranslated region of 69M is identical to a section of UK coding sequence. The DS-1 and the remainder of the 69M 3'-end additional sequences are similar to each other, but neither is similar to any other currently available rotavirus gene sequence. This finding suggests that a process other than homologous duplication is involved in the evolution of these sequences. The widespread occurrence of human and animal rotaviruses with short and super short electropherotypes provides evidence that intragenic and possibly intergenic recombinational events associated with an error-prone viral RNA polymerase may play a role in increasing the genetic repertoire of rotaviruses.

Amino Acid Sequence↗
PubMed1983

Sequence repeats in a polyoma virus DNA region important for gene expression.

The sequenced prototype strains (A2 and A3) of polyoma virus lack sequence duplications characteristic of other papovaviruses. However, we found that five polyoma virus strains (P16, Toronto large plaque, MV, Ts 48, and NG59R) contain tandemly duplicated sequences in a region near the late RNA leader. Although the duplications vary in size (31 to 84 base pairs) and location (between nucleotide [nt] 5068 and nt 5185), the sequence between nt 5114 and nt 5137 is contained within all five duplicated segments. This region is known to be important in polyoma virus early gene expression, and it contains sequences capable of enhancing the expression of nonviral genes. Inspection of the sequences at and around the ends of the repeats indicated that the duplications do not arise by homologous recombination, and there was no indication that a sequence-specific mechanism results in their formation. However, the variation in the structure of the repeats among different polyoma virus strains suggests that these sequence duplications are a recent evolutionary occurrence. The potential biological significance of this variation is discussed.

Base Sequence↗
PubMed1998

The foot-and-mouth disease RNA virus as a model in experimental phylogenetics.

Phylogenetic reconstruction methods are subject to two types of limitations: our knowledge about the true history of organisms and the gross simplification implied in the numerical simulation models of the relationships between them. In such a situation, experimental phylogenetics provides a way to assess the accuracy of the phylogenetic reconstruction methods. Nonetheless, this capacity is only feasible for organisms in which replication and mutation rates are high enough to provide valuable data. On the other hand, experimental phylogenetics also provides insights on the main evolutionary processes acting on viral variability under different population dynamics. Our study with the foot-and-mouth disease virus (FMDV) strongly suggests that the phylogenetic reconstruction methods can infer erroneous phylogenies due to nucleotide convergences between isolates belonging to different experimental lineages. We also point out that the diverse evolutionary mechanisms acting in different experimental dynamics generate alterations and change the frequencies of genetic variants, which can lead to the misinterpretation of the real evolutionary history.

Animals↗
PubMed1997

De novo hepatitis B and C viral infection after liver transplantation.

Hepatitis B (HBV) and hepatitis C (HCV) viral infections often recur after orthotopic liver transplantation (OLT), but viral infections acquired with OLT have not been widely investigated. The aim of the study was to evaluate the incidence, evolution, and diagnostic problems of de novo HBV and HCV infections in liver transplant recipients with long-term follow-up. Altogether 121 transplant recipients entered the study. HBV, HDV, and HCV infections were diagnosed by means of serology and the polymerase chain reaction (PCR). Three patients became hepatitis B surface antigen (HBsAg)-positive after OLT, all of whom showed signs of persistent viral replication. Twelve patients became anti-HCV-positive after OLT: After clearance of passive antibodies, active anti-HCV seroconversion was usually delayed. The viral genome was detected in 9 of 12 patients, with fluctuations of viremia during their follow-up. The other three patients, who were HBsAg-positive before and after OLT, were repeatedly HCV-RNA-negative despite persistent anti-HCV reactivity. Four pre-OLT HBsAg-positive patients had evidence of HBV-related liver transplant disease. The remaining 8 of 12 patients experienced repeated alanine aminotransferase increases more than two times normal after transplant. De novo infections due to primary hepatotropic viruses were frequent after OLT in our experience. Early diagnosis of infection, especially when the HCV is involved, may be problematic and should be taken into account in patients showing persistent aminotransferase abnormalities. Monitoring viral markers and accurate evaluation of biopsy specimens are mandatory. The interference between HBV and HCV might play a role in the replicative cycle of one or both viruses in co-infected patients.

Antibodies, Viral↗
PubMed1989

Mutation rate of the hepadnavirus genome.

An essential factor for charting the evolution of hepadnaviruses is an estimation of the mutation rate of the virus genome during replication in the host. In order to determine the mutation rate of the hepadnavirus genome under defined experimental conditions, we transfected 10 neonatal woodchucks with an infectious molecular clone of woodchuck hepatitis virus (WHV). By 4 months post-transfection, all 10 animals showed serological evidence for WHV infection. Subsequently, 1 animal became chronically infected and was used for further study. At 16 months post-transfection WHV DNA from serum virions was cloned and the nucleotide sequence of three independent progeny genomes compared directly with that of the input recombinant DNA. Although the consensus nucleotide sequence remained unchanged, we found three differences in individual progeny genomes when compared to the parental genome sequence. Thus, we estimate the mutation rate of the WHV genome to be less than or equal to 2 X 10(-4) base substitutions/site/year. This figure is one to two orders of magnitude lower than the mutation rates previously calculated for the positive- and negative-strand RNA viruses, but is similar to the mutation rate of the gag gene which is the most slowly evolving gene of retroviruses. Therefore, we find that the hepadnavirus genome is relatively stable during replication in host tissues when compared to other viruses that lack polymerase-associated proofreading functions.

Animals↗
PubMed1999

Characterization of V3 sequence heterogeneity in subtype C human immunodeficiency virus type 1 isolates from Malawi: underrepresentation of X4 variants.

We have examined the nature of V3 sequence variability among subtype C human immunodeficiency virus type 1 (HIV-1) sequences from plasma-derived viral RNA present in infected men from Malawi. Sequence variability was assessed by direct sequence analysis of the V3 reverse transcription-PCR products, examination of virus populations by a subtype C V3-specific heteroduplex tracking assay (V3-HTA), and selected sequence analysis of molecular clones derived from the PCR products. Sequence variability in V3 among the subtype C viruses was not associated with the presence of basic amino acid substitutions. This observation is in contrast to that for subtype B HIV-1, where sequence variability is associated with such substitutions, and these substitutions are determinants of altered coreceptor usage. Evolutionary variants in subtype C V3 sequences, as defined by the V3-HTA, were not correlated with the CD4 level in the infected person, while such a correlation was found with subtype B V3 sequences. Viruses were isolated from a subset of the subjects; all isolates used CCR5 and not CXCR4 as a coreceptor, and none was able to grow in MT-2 cells, a hallmark of the syncytium-inducing phenotype that is correlated with CXCR4 usage. The overall sequence variability of the subtype C V3 region was no greater than that of the conserved regions of gp120. This limited sequence variability was also a feature of subtype B V3 sequences that do not carry the basic amino acid substitutions associated with altered coreceptor usage. Our results indicate that altered coreceptor usage is rare in subtype C HIV-1 isolates in sub-Saharan Africa and that sequence variability is not a feature of the V3 region of env in the absence of altered coreceptor usage.

Base Sequence↗
PubMed2006

Sequence analysis of coat protein gene of Wuhan nodavirus isolated from insect.

Wuhan nodavirus (WhNV) particles are isometric, non-enveloped, and about 29 nm in diameter. In the previous study, we determine its physiochemical characterization and the nucleotide sequence of the larger genomic segment, RNA1 and identify it a nodavirus. WhNV RNA1 is 3,149 nt in length, encoding protein A, catalytic subunit of RNA-dependent RNA polymerase (RdRp). In this report, we complete the sequence determination of the smaller genomic segment, RNA2 of WhNV. WhNV RNA2 is determined to be 1,562 nt long, containing a 430-amino-acid open reading frame (ORF) encoding the coat protein of WhNV with a calculated molecular mass of 47,856 Da. The homology of the coat protein of WhNV and the homologous proteins of other nodaviruses either alphanodaviruses or betanodaviruses is very low. WhNV coat protein shares the highest identity (24%) with that of Lates calcarifer encephalitis virus (LCEV), a betanodavirus, and shares less than 16% identical amino acids with each of the alphanodaviruses. Furthermore, the prediction of WhNV capsid structure by 3D-PSSM shows that the capsid structure of WhNV resembles that of tomato bushy stunt virus (TBSV), a tombusvirus, which contains two domains, rather than the expected single-domain capsid protein of insect nodaviruses. The phylogenetic analysis indicates that WhNV is the most distantly related of both the alphanodaviruses and betanodaviruses, which provides significant new data for understanding the evolution of the nodavirus family.

Amino Acid Sequence↗
PubMed2004

[Chronic hepatitis C virus infection].

Following acute hepatitis C virus infection (HCV), a significant percentage of patients do not clear the virus and develop a chronic hepatitis C. The symptoms, when they exist, are usually unspecific. Besides, approximately one third of the patients present extrahepatic manifestations of the infection, basically due to the lymphotropism of HCV. Outstanding amongst these, due to their clear association with HCV, are mixed cryoglobulinaemia and the production of autoantibodies (autoAb). Other diseases such as non-Hodgkin lynphoma (NHL) or autoimmune thyroiditis do not have a clearly established association. Although the majority of patients with chronic hepatitis C have slight or moderately high levels and fluctuations of transaminases, as many as one third of those infected can show persistently normal levels of transaminases. The diagnosis of chronic HCV infection is based on serological tests, which detect the presence of antibodies against HCV, and on virological tests that detect RNA of the HCV, which confirm the existence of active infection. Finally, an important topic of chronic HCV infection, following diagnosis, is to ascertain the stage of fibrosis and the degree of inflammation, since both characteristics are very important for predicting the natural evolution and the need for treatment. Nowadays, this information can only be obtained through liver biopsy, which is recommended in patients with chronic HCV infection and high transaminases. Whether liver biopsy should be performed in patients with normal transaminases is still subject of controversy.

Autoimmune Diseases↗
PubMed1994

Fidelity of HIV-1 reverse transcriptase copying a hypervariable region of the HIV-1 env gene.

The unusually high mutation frequency exhibited by the human immunodeficiency virus (HIV) is a major impediment to developing effective vaccines against the virus and to designing analogs that inhibit viral replication. To investigate the molecular basis of HIV hypermutability, we established cell-free assays to measure the fidelity of HIV-1 reverse transcriptase (RT) in copying either DNA or both RNA and DNA templates that contain the hypervariable region 1 of the HIV-1 env gene (V-1). The fidelity of DNA synthesis was measured by repetitively copying the envelope gene (V-1) DNA by HIV-1 RT, followed by cloning and sequencing these newly synthesized DNA products. We found that the error rate of HIV RT copying either RNA or DNA of the env V-1 region is about one misincorporation per 5 kb polymerized. This rate is similar to that found with the M13mp2 forward mutation assay using the lacZ alpha gene as a template. This similarity suggests that the HIV env hypervariable sequence is not inherently hypermutable. The high error rate of HIV RT suggests that misincorporation by this enzyme is a major source of mutations throughout the viral genome and a determinant for rapid viral evolution. The spectrum of mutations produced by HIV RT in vitro partially correlates with the spectrum of HIV mutations observed in AIDS patients. The differences between these spectra highlight the contribution of phenotypic selection during HIV-1 infection. The overall uniformity of misincorporation of HIV-1 RT further suggests an alternative anti-HIV strategy based on increasing viral mutagenesis by nucleotide analogs.

Base Sequence↗
PubMed2005

Hepatitis C virus seroprevalence and genotypes in patients with diffuse connective tissue diseases and spondyloarthropathies.

Many extrahepatic manifestations, including rheumatic diseases, have been reported to be associated with hepatitis C virus (HCV) infection. In order to investigate the prevalence of HCV infection among patients with rheumatic diseases, in the present study we interviewed 367 patients and tested their blood samples for HCV antibodies (anti-HCV) by an enzyme-linked immunosorbent assay. Anti-HCV-reactive samples were retested for confirmation by a line immunoassay and also for HCV RNA detection by the polymerase chain reaction. HCV RNA-positive samples were genotyped by INNO-LIPA. An overall HCV infection prevalence of 1.9% (7/367) was found. Of the 7 HCV-infected patients, 4 had systemic lupus erythematosus and 3 rheumatoid arthritis, resulting in positivity rates of 2.3 and 3.4%, respectively. HCV RNA genotyping revealed the presence of subtypes 1a (57.1%), 1b (28.6%) and 3a (14.3%). The clinical course was favorable for all HCV-infected patients, except one, who died due to renal insufficiency related to lupus nephritis. These results demonstrate a low HCV infection prevalence among the population studied. In the few positive cases, we observed no adverse influence of this infection on the clinical evolution of the rheumatic disease.

Adolescent↗
PubMed2003

Surrogate markers as a guide to evaluate response to antiretroviral therapy.

The development of an increasing number of antiretroviral agents has dramatically reduced HIV-associated morbidity and mortality. However, most of these drugs have been approved through clinical trials where only surrogate markers for clinical endpoints have been used. Ideally, a surrogate marker should be biologically plausible, predictive of disease progression and measurable by standardized assays. Historically, a number of candidate markers have been explored for monitoring the course of HIV infection and response to treatment. While the level of plasma HIV RNA and the absolute numbers of peripheral CD4+ T cells have eventually become the reference markers in clinical practice, several additional parameters are still being evaluated to improve our knowledge of the virus-host interaction, discriminate between apparently equivalent stages and further refine antiretroviral treatment. Advances in molecular methods and growing elucidation of HIV dynamics in vivo have made it possible to consider several molecular virologic parameters as candidate markers for treatment response, including intracellular levels of different HIV RNA species and amount of integrated and unintegrated HIV DNA. Much effort has been recently devoted to the definition of immunological parameters as prognostic markers. The abnormal activation induced by HIV on the immune system represents a major pathogenetic feature of HIV infection. Immune activation may be evaluated by the analysis of activation markers expressed on the cell membrane and by the quantification of soluble plasma molecules released by activated cells. Such markers of immune activation have an important prognostic significance in terms of disease progression and might be suitable for the monitoring and prognosis of antiretroviral therapies. In the late years, the possibility of extending potent antiretroviral therapies to developing countries has raised the need of simple, reliable and cost-effective tests to measure prognostic markers for disease evolution and assessment of therapy efficacy. This review summarizes the benefits and limits of reference and candidate surrogate markers and their integration for optimal antiretroviral therapy.

Animals↗
PubMed1999

Molecular parasites that evolve longer genomes.

Molecular parasites that utilize the replication machinery of cells or of in vitro amplification reactions have previously been characterized. By and large, these parasites have been smaller than the viruses or amplicons that gave rise to them. This is likely because shorter genomes can be replicated more quickly. In contrast, we have identified and characterized parasites of an isothermal amplification reaction that are longer than their parental molecules yet replicate much more efficiently. These results raise interesting questions regarding whether the optimal size of replicators reflects a trade-off between the information encoded in a parasite and the information encoded in the machinery replicating that parasite.

Base Sequence↗
PubMed2002

[Acquisition and loss of modules: the construction set of transposable elements].

Phylogenetic analysis of transposable elements (TEs) allows us to define the relationships between the domains or gene(s) that compose them. Moreover, modules of a few amino-acids can be detected within gag, pol, env genes or within the integrase domain of retrotransposons and transposase of DNA elements. The combination of these observations clearly shows that the evolutionary history of TEs is the outcome of the acquisition and loss of modules with differing origins and histories. This raises the question of the origin of TEs: are they derived from viruses? Are they where viruses come from? Do the basic building bricks come from the prokaryotes, and can they be assembled in the eukaryotes? Are the TEs found in prokaryotes the result of the disintegration of complex elements such as retroelements? Do they evolve from the simplest to the more complex, or are they opportunistic sequences evolving by acquiring and/or losing modules which may be either important or superfluous to their fitness (i.e., their ability to transpose). These are some of the questions that are addressed and discussed in the light of the comparative structures of TEs.

Catalytic Domain↗
PubMed2006

The innate immune response to grass carp hemorrhagic virus (GCHV) in cultured Carassius auratus blastulae (CAB) cells.

Virus infection of mammalian cells activates an innate antiviral immune response characterized by production of interferon (IFN) and the subsequent transcriptional upregulation of IFN-stimulated genes (ISGs) by the JAK-STAT signaling pathway. Here, we report that a fish cell line, crucian carp (Carassius auratus L.) blastulae embryonic (CAB) cells, can produce IFN activity and then form an antiviral state after infection with UV-inactivated grass carp hemorrhagic virus (GCHV), a double-stranded (ds) RNA virus. From UV-inactivated GCHV-infected CAB cells, 15 pivotal genes were cloned and sequenced, and all of them were shown to be involved in IFN antiviral innate immune response. These IFN system genes include the dsRNA signal sensing factor TLR3, IFN, IFN signal transduction factor STAT1, IFN regulatory factor IRF7, putative IFN antiviral effectors Mx1, Mx2, PKR-like, Viperin, IFI56, and other IFN stimulated genes (ISGs) IFI58, ISG15-1, ISG15-2, USP18, Gig1 and Gig2. The identified fish IFN system genes were highly induced by active GCHV, UV-inactivated GCHV, CAB IFN or poly(I).poly(C), and showed similar expression patterns to mammals. The data indicate that an IFN antiviral innate immune response similar to that in mammals exists in the UV-inactivated GCHV-infected CAB cells, and the IFN response contributes to the formation of an antiviral state probably through JAK-STAT signaling pathway. This study provides strong evidence for existence of IFN antiviral innate immune response in fish, and will assist in elucidating the origin and evolution of vertebrate IFN system.

Animals↗