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PubMed2005

Detection of hepatitis B virus genotypes and mutants: current status.

Characterization results of the hepatitis B virus (HBV) genome before, during and after antiviral treatment have changed in the last year for a number of reasons. First of all, with the introduction of more nucleoside and nucleotide antiviral therapies, it has become clear that variants or mutants do emerge in time. Viral genomic changes in the HBV polymerase gene can result in a direct antiviral effect, but compensatory mutations can also be identified during prolonged treatment periods. Furthermore, there is an increasing number of reports suggesting that HBV genotypes can be related to, for example, disease progression or the effect of antiviral treatment itself (alpha-interferon or lamivudine). Combined with HBV DNA viral load monitoring, an increase in viral load or a limited reduction during treatment is indicative of genomic changes related to resistance. However, these genomic changes can also be present in the absence of an increase in HBV DNA. Methodologies for the detection of these variants, as well as the determination of genotypes, are rather straightforward. Sequence analysis is time-consuming and expensive, but provides the most information, particularly if not all information on mutations related to antiviral resistance is known. However, the sensitivity of direct sequencing for the presence of minor variant populations is poor, and no mixtures of variant populations are, in general, detected. The ability to detect minor populations and, if possible, even quantify them, gives more insightful information on the dynamic evolution of the virus itself. Antiviral treatment can result in the appearance of more than one population of variants, which can be present for a prolonged period of time, and even remain undetected with current technologies. However, screening specifically for these variant populations before starting treatment for so-called untreated patients (who have received no antiviral treatment for, e.g., 6 months) has already shown that the effects of treatment can be biased. Furthermore, the detection of more dynamic viral populations - including both wild-type and resistant variants - during, but also after therapy, does provide helpful information in the analysis of virological data. Technologies enabling the detection and quantification of these variant populations are presented and discussed.

Antiviral Agents↗

PubMed1993

Analysis of the biased distribution of topoisomerase I break sites on replicating simian virus 40 DNA.

We previously mapped the locations of breaks introduced by eukaryotic topoisomerase I (topo I) in replicating simian virus 40 (SV40) DNA and observed an approximate 3:1 bias in the distribution of the break sites for the template strand for discontinuous DNA synthesis. In the present study, this bias has been confirmed by the mapping of additional sites utilizing a standard primer extension assay and a sensitive repetitive primer extension (RPE) method. No new sites could be detected on either strand of SV40 by the RPE method, despite the 10 to 20 fold greater sensitivity of the technique. To investigate the nature of the bias, a detailed analysis of the SV40 DNA sequence was undertaken. A set of 17 pentanucleotide sequences derived from those sites observed to be broken in the viral DNA extracted from SV40-infected cells define an in vivo consensus sequence. We show that the observed strand bias is likely due to the intrinsic asymmetric distribution of these consensus sequences on the two strands of SV40 DNA. To confirm these observations, double-stranded oligonucleotides containing previously identified in vivo topo I break sites were introduced in both orientations into SV40 to generate insertion mutants. Mapping experiments utilizing these mutants revealed that the inserted topo I break sites were broken in vivo regardless of their orientation, confirming that the SV40 sequence is the major, if not the sole determinant, of the observed strand bias. The possible origins of the strand bias are discussed in relation to the evolution of the virus.

Animals↗

PubMed1998

The nature of human immunodeficiency virus type 1 strand transfers.

The diploid nature of human immunodeficiency virus type 1 (HIV-1) suggests that recombination serves a central function in virus replication and evolution. A system was developed to examine HIV-1 strand transfers, including the obligatory DNA primer strand transfers as well as recombinational crossovers during reverse transcription. Sequence heterogeneity between different strains of HIV-1 was exploited for examining primer transfer events. Both intra- and intermolecular primer transfers were observed at similar frequencies during minus-strand DNA synthesis, whereas primer transfers during plus-strand DNA synthesis were primarily intramolecular. Sequence analysis of long terminal repeats from progeny proviruses also revealed a high rate of homologous recombination during minus-strand synthesis, corresponding to an overall rate of approximately three crossovers per HIV-1 genome per cycle of replication. These results imply that both viral genomic RNAs serve as templates during HIV-1 reverse transcription and that primer strand transfers and recombination may contribute substantially to the rapid genetic variation of HIV-1.

Base Sequence↗

PubMed2000

High rate of recombination throughout the human immunodeficiency virus type 1 genome.

The diploid nature of human immunodeficiency virus type 1 (HIV-1) indicates that recombination serves a central function in virus replication and evolution. Previously, while examining the nature of obligatory primer strand transfers during reverse transcription, a high rate of recombination was observed at the ends of the viral genome within the viral long terminal repeats, prompting the following question: does recombination occur at a high rate throughout the genome? To address this question, two vectors based upon different strains of HIV-1 were utilized. The vectors were comprised predominantly of autologous HIV-1 sequence and were approximately the same size as the parental genome. The proviral progeny of heterodimeric virions were analyzed after a single cycle of replication, and the sequence heterogeneity between the two strains allowed direct examination of recombination crossovers. The results obtained indicate that HIV-1 undergoes approximately two to three recombination events per genome per replication cycle. These results imply that both HIV-1 RNAs are typically utilized during reverse transcription and that recombination is an important aspect of HIV-1 replication.

Cell Line↗

PubMed2025

HI-FEVER: a Nextflow pipeline for the high-throughput discovery and annotation of endogenous viral elements.

SUMMARY: Endogenous viral elements (EVEs) offer valuable insights into virus and host evolution, but their detection remains computationally and biologically challenging. We present HI-FEVER, a user-friendly Nextflow pipeline for the discovery of EVEs in eukaryotic host genomes. HI-FEVER is highly parallelizable and customizable, ensuring computational efficiency while allowing researchers to fine-tune parameters to their specific needs. Its output provides a comprehensive analysis of discovered EVEs, including detailed annotations which can provide evolutionary insights. HI-FEVER scales seamlessly to handle millions of viral protein queries across multiple host genomes on both laptops and high-performance computing nodes. AVAILABILITY AND IMPLEMENTATION: The HI-FEVER source code is available on GitHub at https://github.com/PaleovirologyLab/hi-fever. Minimal reference databases, test datasets and benchmarking results are hosted on the Open Science Framework at https://osf.io/y357r. A detailed wiki is available at https://github.com/PaleovirologyLab/hi-fever/wiki, including usage instructions, parameter descriptions, and guidance on interpreting outputs. The pipeline includes a Pixi environment compatible with Conda and Apptainer containerization, and Docker images. HI-FEVER has been tested on Linux, Windows (via WSL2), and macOS (Intel and ARM64).

Software↗

PubMed1994

The alphaviruses: gene expression, replication, and evolution.

The alphaviruses are a genus of 26 enveloped viruses that cause disease in humans and domestic animals. Mosquitoes or other hematophagous arthropods serve as vectors for these viruses. The complete sequences of the +/- 11.7-kb plus-strand RNA genomes of eight alphaviruses have been determined, and partial sequences are known for several others; this has made possible evolutionary comparisons between different alphaviruses as well as comparisons of this group of viruses with other animal and plant viruses. Full-length cDNA clones from which infectious RNA can be recovered have been constructed for four alphaviruses; these clones have facilitated many molecular genetic studies as well as the development of these viruses as expression vectors. From these and studies involving biochemical approaches, many details of the replication cycle of the alphaviruses are known. The interactions of the viruses with host cells and host organisms have been exclusively studied, and the molecular basis of virulence and recovery from viral infection have been addressed in a large number of recent papers. The structure of the viruses has been determined to about 2.5 nm, making them the best-characterized enveloped virus to date. Because of the wealth of data that has appeared, these viruses represent a well-characterized system that tell us much about the evolution of RNA viruses, their replication, and their interactions with their hosts. This review summarizes our current knowledge of this group of viruses.

Alphavirus↗

PubMed1999

Antiretroviral therapy in 1999 for antiretroviral-naive individuals with HIV infection.

The choice of initial antiretroviral regimen for treating people infected with HIV is crucial to successful long-term control of virus replication. Potent antiretroviral therapy substantially suppresses viral replication as measured by plasma HIV RNA levels to below limits of detection: the current standard of care is usually a combination of at least three drugs and frequently includes a protease inhibitor, or alternatively a non-nucleoside reverse transcriptase inhibitor (nnRTI). Patients who have low CD4+ cell counts (< or = 200 CD4+ cells/mm3) or high plasma HIV RNA levels (> or = 100,000 copies/ml) may not attain maximal suppression of HIV replication when treated with current regimens and may require more aggressive therapy. In contrast, patients with relatively normal CD4+ cell counts and low to non-measurable levels of plasma HIV RNA over prolonged periods (i.e., slow or non-progressors) may not require immediate antiretroviral therapy. These individuals should reconsider treatment when either the CD4+ cell count declines or the HIV RNA level increases. Early and potent antiretroviral therapy should provide more durable virological and clinical benefits for many patients, especially if they receive sufficient counselling and support to aid adherence to the treatment regimen. The optimum time to initiate antiretroviral therapy is not well established, but to maximise the recovery of the immune system and the virological and clinical benefits, initiation of therapy is generally recommended for individuals who have symptoms or those with plasma HIV RNA levels > 5000-10,000 copies/ml, or CD4+ cell counts < 500 cells/mm3. The current choice of initial antiretroviral regimens includes two nucleoside reverse transcriptase inhibitors (nRTI) with a potent, well-tolerated HIV-1 protease inhibitor or nnRTI. Recent short-term activity data (24-week comparative clinical trial data) indicate that regimens combining three nRTI, including abacavir, could also be considered. Other emerging combination regimens for consideration include two HIV-1 protease inhibitors with one or two nRTI, or a combination of drugs from all current categories (e.g., nRTI with a nnRTI and HIV-1 protease inhibitor). The goal of antiretroviral therapy is to maximise suppression of HIV replication and thereby prevent or delay viral resistance, restore immunological function and improve clinical outcome. Since evolution of the virus towards resistance can occur with plasma HIV RNA levels between 50 and 500 copies/ml, current standards for best suppression of HIV replication have shifted to declines in plasma HIV RNA to < 50 copies/ml. In addition, non-adherence to any regimen is associated with the greatest risk for virological failure. Therefore, both the decision to initiate therapy and the choice of initial therapy should be carefully weighted and balanced with the long-term implications of antiretroviral therapy.

Anti-HIV Agents↗

PubMed1999

Phylogenetic evidence for recombination in dengue virus.

A split decomposition analysis of dengue (DEN) virus gene sequences revealed extensive networked evolution, indicative of recombination, among DEN-1 strains but not within serotypes DEN-2, DEN-3, or DEN-4. Within DEN-1, two viruses sampled from South America in the last 10 years were identified as recombinants. To map the breakpoints and test their statistical support, we developed a novel maximum likelihood method. In both recombinants, the breakpoints were found to be in similar positions, within the fusion peptide of the envelope protein, demonstrating that a single recombination event occurred prior to the divergence of these two strains. This is the first report of recombination in natural populations of dengue virus.

Dengue↗

PubMed1998

Evolution of hypervariable region 1 of hepatitis C virus in primary infection.

The hypervariable region 1 (HVR-1) of the putative envelope encoding E2 region of hepatitis C virus (HCV) RNA was analyzed in sequential samples from three patients with acute type C hepatitis infected from different sources to address (i) the dynamics of intrahost HCV variability during the primary infection and (ii) the role of host selective pressure in driving viral genetic evolution. HVR-1 sequences from 20 clones per each point in time were analyzed after amplification, cloning, and purification of plasmid DNA from single colonies of transformed cells. The intrasample evolutionary analysis (nonsynonymous mutations per nonsynonymous site [Ka], synonymous mutations per synonymous site [Ks], Ka/Ks ratio, and genetic distances [gd]) documented low gd in early samples (ranging from 2. 11 to 7.79%) and a further decrease after seroconversion (from 0 to 4.80%), suggesting that primary HCV infection is an oligoclonal event, and found different levels and dynamics of host pressure in the three cases. The intersample analysis (pairwise comparisons of intrapatient sequences; rKa, rKs, rKa/rKs ratio, and gd) confirmed the individual features of HCV genetic evolution in the three subjects and pointed to the relative contribution of either neutral evolution or selective forces in driving viral variability, documenting that adaptation of HCV for persistence in vivo follows different routes, probably representing the molecular counterpart of the viral fitness for individual environments.

Adolescent↗

PubMed2003

The origin, emergence and evolutionary genetics of dengue virus.

Dengue is one of the most important emerging viruses, posing a threat to one-third of the global human population. Herein we show how the comparative analysis of gene sequence data has shed light on the origin and spread of dengue virus, as well as on the evolutionary processes that structure its genetic diversity. This reveals that dengue virus has a relatively recent evolutionary history, with the four serotypes originating approximately 1000 years ago and only establishing endemic transmission in humans in the last few hundred years. However, its place of origin remains uncertain as does the extent of genetic and phenotypic diversity present in the sylvatic (primate) transmission cycle. Although there is some evidence that viral strains differ in key phenotypic features such as virulence, and for positive selection at immunologically important sites, it seems likely that stochastic processes also play a major role in shaping viral genetic diversity, with lineage extinction a common occurrence. A more complete understanding of the evolution and epidemiology of dengue virus, particularly with respect to the aetiology of severe disease, will require large-scale prospective studies and the comparative analysis of complete genome sequences.

Animals↗

PubMed2001

Population genetic analysis of the protease locus of human immunodeficiency virus type 1 quasispecies undergoing drug selection, using a denaturing gradient-heteroduplex tracking assay.

Monitoring the evolution of human immunodeficiency virus type 1 (HIV-1) drug resistance requires measuring the frequency of closely related genetic variants making up the complex viral quasispecies found in vivo. In order to resolve both major and minor (>/=2%) protease gene variants differing by one or more nucleotide substitutions, we analyzed PCR products derived from plasma viral quasispecies by using a combination of denaturing gradient gel electrophoresis and DNA heteroduplex tracking assays. Correct population sampling of the high level of genetic diversity present within viral quasispecies could be documented by parallel analysis of duplicate, independently generated PCR products. The composition of genetically complex protease gene quasispecies remained constant over short periods of time in the absence of treatment and while plasma viremia fell >100-fold following the initiation of protease inhibitor ritonavir monotherapy. Within a month of initiating therapy, a strong reduction in the genetic diversity of plasma viral populations at the selected protease locus was associated with rising plasma viremia and the emergence of drug resistance. The high levels of protease genetic diversity seen before treatment reemerged only months later. In one patient, reduction in genetic diversity at the protease gene was observed concomitantly with an increase in diversity at the envelope gene (E. L. Delwart, P. Heng, A. Neumann, and M. Markowitz, J. Virol. 72:2416-2421, 1998), indicating that opposite population genetic changes can take place in different HIV-1 loci. The rapid emergence of drug-resistant HIV-1 was therefore associated with a strong, although only transient, reduction in genetic diversity at the selected locus. The denaturing gradient-heteroduplex tracking assay is a simple method for the separation and quantitation of very closely related, low-frequency, genetic variants within complex viral populations.

Biological Evolution↗

PubMed2003

Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients.

The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.

Adult↗

PubMed2006

Hepatitis C databases, principles and utility to researchers.

Part of the effort to develop hepatitis C-specific drugs a nd vaccines is the study of genetic variability of allpublicly available HCV sequences. Three HCV databases are currently available to aid this effort and to provide additional insight into the basic biology, immunology, and evolution of the virus. The Japanese HCV database (http://s2as02.genes.nig.ac.jp) gives access to a genomic mapping of sequences as well as their phylogenetic relationships. The European HCV database (http://euhcvdb.ibcp.fr) offers access to a computer-annotated set of sequences and molecular models of HCV proteins and focuses on protein sequence, structure and function analysis. The HCV database at the Los Alamos National Laboratory in the United States (http://hcv.lanl.gov) provides access to a manually annotated sequence database and a database of immunological epitopes which contains concise descriptions of experimental results. In this paper, we briefly describe each of these databases and their associated websites and tools, and give some examples of their use in furthering HCV research.

Biomedical Research↗

PubMed1999

Group II nucleopolyhedrovirus subgroups revealed by phylogenetic analysis of polyhedrin and DNA polymerase gene sequences.

Two major clades, designated Groups I and II, of nucleopolyhedroviruses (NPVs) from lepidopteran hosts have been previously identified. To reveal more detailed relationships, a series of DNA polymerase nucleotide sequences from the taxa MbMNPV, SeMNPV, HzSNPV, HearNPV, SpltNPV, BusuNPV, and OranNPV have been determined using a polymerase chain reaction (PCR)-based approach. This technique enabled gene sequence determination using microliter samples of NPV-infected insect cadavers. Polyhedrin genes from HearNPV, OranNPV, SeMNPV, and SpltNPV were also isolated and sequenced using a similar approach. These sequences, together with other database entries, were aligned for positional homology of peptide sequences. Phylogenetic analysis of DNA polymerase molecular sequence alignments supports LdMNPV as a taxon of Group II and three Group II subclades, designated A, B, and C. Comparison of DNA polymerase trees with those estimated from occlusion protein molecular sequences enabled identification of three subclades of Group II. These are Subgroup II-A [MbMNPV, LeseNPV, MacoNPV, PaflNPV, SeMNPV, SpltNPV (India isolate), SfMNPV]; Subgroup II-B [SpliNPV, SpltNPV (Japan isolate), SpltNPV (Queensland isolate), and possibly HzSNPV, HearNPV, and ManeNPV], and Subgroup II-C [OpSNPV, OranNPV (S-type), BusuNPV (S-type), and possibly EcobNPV (S-type)]. Notably, all Subgroup II-A taxa are from noctuid hosts. Correlations of virus and host evolution within Group II taxa are discussed. The methods and data developed in this study will allow rapid sequencing of NPV DNA polymerase genes.

Amino Acid Sequence↗

PubMed2002

Sequence diversity of the capsid gene and the nonstructural gene NS2B of dengue-3 virus in vivo.

Previously, we studied the envelope (E) gene of dengue virus and reported that dengue-3 virus is present as a quasispecies. To investigate the extent of intrahost sequence variation of other dengue viral genes, we examined in this study the capsid (C) gene and the nonstructural gene, NS2B, derived directly from plasma dengue viruses from 18 confirmed dengue-3 patients. Using reverse transcription-PCR, multiple clones of a 360-nucleotide region covering the C gene and of a 404-nucleotide region covering the NS2B gene from each patient were completely sequenced and analyzed. Our findings of the intrahost sequence variation of the C and the NS2B genes (mean pairwise p-distance: 0.12 to 1.02%, and 0.16 to 1.20%, respectively) demonstrate the quasispecies structure of dengue virus in vivo. A linear relationship was found between the extent of sequence variation of the C and NS2B proteins, suggesting that intrahost sequence variation of dengue-3 virus is likely to reflect genetic drift. The extent of intrahost sequence variation observed is in the same range as that of acute human immunodeficiency virus or hepatitis C virus infection, indicating that the random mutation frequency of dengue virus is similar to that of other RNA viruses in vivo. Consistent with a previous report of the E gene, the observations of genome-defective clones in both the C and the NS2B genes (3.9 and 5.0% of the clones, respectively) suggest a higher frequency of defective viruses in vivo. These findings would add to our understanding of the evolution of dengue-3 virus.

Adult↗

PubMed1977

Herpesvirus group antibodies in children with Hodgkin's disease.

During the period of three years ((1972-1974), serum samples from 60 patients (children and adolescents) with lympho-hematopoietic system diseases were examined for antibodies to all four human herpesviruses. Among these were 26 active Hodgkin's disease (AHD) patients and 6 HD patients with a minimum five years' remission. Simultaneously matched controls (age, sex) of AHD patients were examined. Antibody levels against the viral capsid antigen of Epstein-Barr virus (EBV/VCA) in AHD patients were significantly higher, with overrepresentation of higher titres (greater than or equal to 1:160), than in matched controls. The lowest EBV/VCA antibody titres were in the leukemia-non-Hodgkin's lymphoma patients. We could not prove any significant relationship between cytomegalovirus or herpes simplex virus type 1 antibody titres and AHD or any other disease of lympho-hematopoietic system. The varicella-zoster virus antibody titres in AHD patients were significantly higher than in matched controls. No significant differences in antibodies against EBV/VCA and the other human herpes viruses between the evolution and remission period of AHD patients could be detected. No differences in EBV/VCA antibody titres were observed between the healthy school-children aged 10 to 15 years who were and who were not in contact with a HD patient.

Adolescent↗

PubMed2006

Sequence analysis of a canine parvovirus isolated from a red panda (Ailurus fulgens) in China.

Canine parvovirus (CPV) was first recognized in the late 1970 s in dogs and has mutated and spread throughout the world in canid and felid species since then. In this study, a novel CPV was isolated from the endangered red panda (Ailurus fulgens) in China. Nucleotide and phylogenetic analysis of the capsid protein VP2 gene classified the red panda parvovirus (RPPV) as a CPV-2a type. Substitution of Val for Gly at the conserved 300 residue in RPPV presents an unusual variation in the CPV-2a amino acid sequence and is further evidence for the continuing evolution of the virus. The 300 residue is important in distinguishing the antigenicity and host range of CPVs. The clinical significance and population impact of RPPV infection in captive red pandas in China is unknown and is an important topic for future research.

Ailuridae↗

PubMed1989

The structure of antiviral agents that inhibit uncoating when complexed with viral capsids.

The tertiary structure of most icosahedral viral capsid proteins consists of an eight-stranded antiparallel beta-barrel with a hydrophobic interior. In a group of picornaviruses, this hydrophobic pocket can be filled by suitable organic molecules, which stop viral uncoating after attachment and penetration into the host cell. The antiviral activity of these agents is probably due to increased rigidity of the capsid protein, thereby inhibiting disassembly. The hydrophobic pocket may be an essential functional component of the protein and may have been conserved in the evolution of many viruses from a common precursor. Since eight-stranded anti-parallel beta-barrels, with a topology as in viral capsid proteins, are not generally found in other proteins involved in cell metabolism, antiviral agents that bind in the interior of viral capsid proteins are likely to be more virus-specific and less cytotoxic. Furthermore, the greatest conservation of viral capsid proteins occurs within this pocket, whereas the least conserved part is the antigenic exterior. Thus, compounds that bind to such a pocket are likely to be effective against a broader group of serologically distinct viruses. Discovery of antiviral agents of this type depends on designing compounds that can enter and fit snugly into the hydrophobic pocket of a particular viral capsid protein.

Antiviral Agents↗