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At least 667 records · Page 37Linked to original sources
PubMed2000

DNA of nonhuman primates harbors hepatitis C-virus-specific sequences of its 5'-non-coding region (5'-NCR).

The DNA from PBMCs of both hepatitis C virus (HCV)-positive patients and healthy HCV-negative human individuals tested thus far contains essential parts--up to 272/341 nucleotides--of the HCV 5'-non-coding region (5'-NCR). These findings bring up the question of the possible evolutionary background of these sequences. Therefore, using the same methodology, we looked for the same sequences in animals closely related to man, i.e., in nonhuman primates (two chimpanzees, one orang-utan, one Debrazza monkey, two New World monkey species and a prosimian). The DNA from PBMCs of the studied animals belonging to nonhuman primates contains essential parts--up to 272/341 nucleotides--of the HCV 5'-non-coding region (5'-NCR). A common sequence of 82 nucleotides is contained in the DNA of all the tested animals but only the chimpanzee's DNA harbors the same, longer sequence region of 272/341 nucleotides of the 5'-NCR found in human DNA. The results may provide a clue as to the possible origin of parts of the IRES containing sequence area of the HCV.

Animals↗
PubMed2005

Marine T4-type bacteriophages, a ubiquitous component of the dark matter of the biosphere.

Tailed bacteriophages are the most abundant biological entities in marine environments. However, most of these marine phages are uncharacterized because few of their hosts have been cultivated. To learn more about such phages, we designed a set of degenerate PCR primers for phage T4 g23, which encodes the major capsid protein in all of the T4-type phages, an important family of the tailed phage. These primers were used to amplify g23-related sequences from diverse marine environments (fjords and bays of British Columbia, the eastern Gulf of Mexico, and the western Arctic Ocean) revealing a remarkable level of molecular diversity, which in some cases was correlated with morphological variation of the virions. Phylogenetic analysis showed that although some of these sequences were closely related to well studied subgroups of the T4-type phage, such as the T-evens, the majority of them belong to five previously uncharacterized subgroups. These data indicate that the host range of T4-type phages is much broader than previously imagined and that the laboratory isolate T4 belongs to a phage family that is extraordinarily widespread and diverse in the biosphere.

Amino Acid Sequence↗
PubMed2003

Analysis of an orf virus chemokine-binding protein: Shifting ligand specificities among a family of poxvirus viroceptors.

We identify a secreted chemokine inhibitor encoded by orf virus (ORFV), the prototypic poxvirus of the Parapoxvirus genus, and show that it is related to the poxvirus type II CC-chemokine-binding proteins (CBP-II) produced by members of the Orthopoxvirus and Leporipoxvirus genera. The ORFV chemokine-binding protein (CBP) is functionally similar to the CBP-II proteins in its ability to bind and inhibit many CC-chemokines with high affinity. However, unlike CBP-II, the ORFV CBP also binds with high affinity to lymphotactin, a member of the C-chemokine family, demonstrating that the ORFV CBP possesses an altered binding specificity. Interestingly, the amino acid sequence of ORFV CBP more closely resembles the granulocyte-macrophage colony-stimulating factor/IL-2 inhibitory factor also produced by ORFV, implicating the granulocyte-macrophage colony-stimulating factor/IL-2 inhibitory factor protein as a highly diverged, but related, member of the CBP-II protein family. Notably, these findings suggest that the genes that encode these proteins derive from a common poxvirus ancestral gene that has since been modified in binding specificity during speciation of the poxvirus genera. Overall, these findings illustrate the concept of evolution of viral proteins at the biophysical and molecular interface.

Amino Acid Sequence↗
PubMed2001

Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons.

Transmission of HIV-1 with reduced susceptibility to antiretroviral drugs raises public health concerns. Through surveillance of drug-resistant HIV-1 in 603 treatment-naive, recently diagnosed HIV-1-infected persons, we identified a distinct group of viruses that have mutations at codon 215 of the reverse transcriptase (RT) gene that are different from either the wild-type (WT) T or the zidovudine (AZT)-selected T215Y/F. These mutations included 215D/C/S and were found in 20 patients (3.3%). The 215D, 215C, and 215S mutations differ from 215Y by a 1-nt change compared with 2 nt for the WT T215 and likely represent revertants of 215Y. These viruses all were found to have WT susceptibility to AZT, and all replicated efficiently as WT HIV-1(T215). However, differences in fitness among HIV-1(215D), HIV-1(215C), and HIV-1(215S) were seen when RT backgrounds were changed, demonstrating a role of the RT background in the selection of these revertants. In vitro selection with AZT showed that HIV-1(215D) and HIV-1(215C) acquired 215Y more rapidly than did WT HIV-1(T215), likely reflecting the need for only 1-nt change to evolve to 215Y. Our study demonstrates that HIV-1 with unusual mutations at codon 215 replicate efficiently, have WT susceptibility, and are commonly found in treatment-naive persons. The increased ability for selecting resistance mutations defines this class of WT HIV-1 and highlights the higher potential of these viruses to compromise the efficacy of antiretroviral therapy.

Anti-HIV Agents↗
PubMed1999

Coalescent estimates of HIV-1 generation time in vivo.

The generation time of HIV Type 1 (HIV-1) in vivo has previously been estimated using a mathematical model of viral dynamics and was found to be on the order of one to two days per generation. Here, we describe a new method based on coalescence theory that allows the estimate of generation times to be derived by using nucleotide sequence data and a reconstructed genealogy of sequences obtained over time. The method is applied to sequences obtained from a long-term nonprogressing individual at five sampling occasions. The estimate of viral generation time using the coalescent method is 1.2 days per generation and is close to that obtained by mathematical modeling (1.8 days per generation), thus strengthening confidence in estimates of a short viral generation time. Apart from the estimation of relevant parameters relating to viral dynamics, coalescent modeling also allows us to simulate the evolutionary behavior of samples of sequences obtained over time.

DNA, Viral↗
PubMed2003

Clinical implications of HIV-1 drug resistance in the neurological compartment.

The tropism of human immunodeficiency virus type 1 (HIV-1) for the central nervous system (CNS) develops early during the course of the infection. Potent antiretroviral therapy has been demonstrated to be effective in controlling the replication of HIV-1 in cerebrospinal fluid (CSF), even though a variable response in this compartment compared with that in plasma has been observed. Different concentrations of antiretroviral drugs are found in CSF and the use of antiretroviral drugs penetrating across the blood-brain barrier is considered to be required for controlling CNS infection in advanced patients, particularly in those with neurological disorders. The compartmentalization of HIV-1 infection in the CNS may affect the treatment response, which may cause a different evolution of viral drug resistance in the 2 compartments. Although HIV-1 resistance testing in CSF is not recommended for the routine management of patients with virological failure, treatment decisions in patients with neurological disorders may require knowledge of the resistance profile of the virus in the CSF.

AIDS Dementia Complex↗
PubMed1999

Quantification of JC virus DNA in the cerebrospinal fluid of patients with human immunodeficiency virus-associated progressive multifocal leukoencephalopathy--a longitudinal study.

In progressive multifocal leukoencephalopathy (PML) the JC virus (JCV) load in the cerebrospinal fluid (CSF) is discussed as a parameter for disease progression. To investigate the evolution of viral shedding into the CSF, the JCV DNA concentration was quantified by competitive polymerase chain reaction (PCR) in multiple CSF samples from prior to and during an unsuccessful intrathecal salvage therapy in 2 human immunodeficiency virus-infected patients with biopsy-proven PML. With continuous clinical progression the virus load varied considerably intra- and interindividually, ranging from nondetectable to 1.2x108 genome equivalents/10 microliter CSF. Whereas an overall increase during progressive disease was confirmed, the virus burden was either constant or fluctuated irregularly during the intermediate stage of disease. This shows a variability of viral shedding during active disease that must be taken into account when the JCV load is measured by quantitative PCR for both the diagnosis of PML and monitoring under investigational treatment.

AIDS-Related Opportunistic Infections↗
PubMed2000

Antiretroviral resistance mutations in human immunodeficiency virus type 1 reverse transcriptase and protease from paired cerebrospinal fluid and plasma samples.

Twenty-four adults infected with human immunodeficiency virus type 1 (HIV-1) with central nervous system symptoms were studied for antiretroviral resistance mutations in HIV-1 RNA obtained from paired cerebrospinal fluid (CSF) and plasma samples. Paired sequences were obtained from 21 and 13 patients for reverse transcriptase (RT) and for protease, respectively. Mutations conferring resistance to the RT inhibitors zidovudine, lamivudine, or nevirapine were detected in 14 patients, including 11 pretreated and 3 drug-naive subjects. The mutation patterns in the 2 compartments were different in most patients. Genotypic resistance to protease inhibitors was detected in both plasma and CSF from 1 patient treated with multiple protease inhibitors. However, accessory protease inhibitor resistance mutations at polymorphic sites were different in plasma and CSF in several patients. Partially independent evolution of viral quasispecies occurs in plasma and CSF, raising the possibility that compartmentalization of drug resistance may affect response to antiretroviral treatment.

Adult↗
PubMed2000

Molecular evolutionary analysis of the complete nucleotide sequence of hepatitis B virus (HBV) in a case of HBV infection acquired through a needlestick accident.

To elucidate needlestick transmission of hepatitis B virus (HBV), strains isolated from 1 physician who acquired HBV infection through a needlestick accident and 3 patients with chronic hepatitis B (donor patients A, B, and C) were tested using molecular evolutionary analysis based on full-length HBV genomic sequences. Nucleotide sequences of these isolates were aligned with 55 previously reported full-length genomic sequences. Genetic distances were estimated using the 6-parameter method, and phylogenetic trees were constructed using the neighbor-joining method. Strains isolated from patient A and the recipient pair were clustered within a closer range of evolutionary distances than were strains recovered from the recipient pair and patients B and C. Furthermore, strains from patient A and the recipient were also clustered on the S gene sequences of HBV. These results demonstrated that patient A alone was the source of direct transmission to the recipient. This approach can be used to investigate the transmission route of HBV.

Adult↗
PubMed2006

Persistence of HIV-1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy can be explained by compensatory fixation.

OBJECTIVE: To investigate the mechanism explaining the persistence of human immunodeficiency virus (HIV) type 1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy. METHODS: Longitudinal genotypic analyses were performed on sequential samples obtained from 2 HIV-1-infected patients who had stopped PI therapy for 4 years. Replication capacity (RC) was determined using recombinant viruses. Subsequently, the effect that changing individual protease mutations back to wild type has on RC was analyzed. RESULTS: We observed prolonged persistence (up to 4 years) of viruses with multiple protease mutations after PI therapy was stopped, despite the fact that the RC of the viruses was severely reduced. Forcing the virus to evolve toward wild type by changing individual protease mutations to wild type was unsuccessful, because all variants displayed a decreased RC in comparison with that of their predecessors. CONCLUSIONS: We propose compensatory fixation as a mechanism for the in vivo persistence of variants with multiple PI-resistance mutations in the absence of PI therapy. Viruses with multiple PI mutations have (partially) compensated for the initial loss in RC. Therefore, reversion of a single mutation causes a (further) reduction in RC and, as a consequence, the route to wild type is blocked.

Amino Acid Sequence↗
PubMed2000

HTLV type I/II in British Columbia Amerindians: a seroprevalence study and sequence characterization of an HTLV type IIa isolate.

It has been established that the human T cell lymphotropic viruses type I and II (HTLV-I and HTLV-II) are both present in some indigenous peoples of the Americas. While HTLV-I has been identified in coastal British Columbia Indians (BCIs), HTLV-II has not been previously reported in the BCIs or other Canadian Amerindians. The prevalence of HTLV-I and HTLV-II in these populations has not been extensively studied. In this article, we examine a group of BCIs from Vancouver Island who belong to the Nuu-Chah-Nulth and are known to have an increased incidence of rheumatic disease. In 494 serum samples from this tribe, the levels of prevalence of HTLV-I and HTLV-II were 2.8 and 1.6%, respectively. No association could be made between arthropathy and HTLV-I infection. In addition, we characterized an HTLV-II isolate of a BCI from the coastal mainland of British Columbia and with a history of intravenous drug abuse. This case represents the first molecular characterization of a Canadian Amerindian HTLV-II isolate: a subtype IIa virus with phylogenetic affinity for intravenous drug user isolates and containing an extended form of the Tax protein. These results are consistent either with this strain having been sampled from a polymorphic ancestral pool of HTLV-II that gave rise to the current epidemic spread of this virus by intravenous drug use and sexual transmission, or with its being "back-transmitted" into the BC Amerindian population in association with intravenous drug use.

Base Sequence↗
PubMed2000

Limited heterogeneity of HIV type 1 in infected mothers correlates with lack of vertical transmission.

The human immunodeficiency virus type 1 (HIV-1) envelope V3 region sequences of peripheral blood mononuclear cell DNA were analyzed from three nontransmitting mothers (infected mothers who failed to transmit HIV-1 to their infants in the absence of antiretroviral therapy), including one mother with two deliveries, and compared with the sequences of seven previously analyzed transmitting mothers. The coding potential of the envelope open reading frame, including several patient-specific amino acid motifs and previously described molecular features across the V3 region, were highly conserved. There was a low degree of heterogeneity within the sequences of each nontransmitting mother compared with the sequences of transmitting mothers. In addition, the estimates of genetic diversity of nontransmitting mother sequences were significantly lower compared with transmitting mother sequences. Phylogenetic analysis showed that the sequences of each nontransmitting mother formed distinct clusters that were well discriminated from each other and the sequences of seven transmitting mothers. In conclusion, a low degree of HIV-1 genetic heterogeneity in these infected mothers correlates with lack of vertical transmission; this finding may be useful in developing strategies for further prevention of maternal-fetal transmission.

Amino Acid Sequence↗
PubMed2003

Evolutionary characteristics of HIV type 1 variants resistant to protease inhibitors in the absence of drug-selective pressure.

To understand the evolutionary characteristics of HIV-1 variants resistant to protease inhibitors (PI), the replicating plasma virus was analyzed in three patients shifted to PI-sparing regimen after virological failure. The dynamic features of carryover mutations associated with PI resistance in the absence of selective pressure on the protease gene indicate that viral variants resistant to reverse transcriptase inhibitors and bearing mutations of the protease sequence can maintain efficient replication capacity in vivo.

Drug Resistance, Viral↗
PubMed1996

Genetic variability and function of the long terminal repeat from syncytium-inducing and non-syncytium-inducing human immunodeficiency virus type 1.

We analyzed sequence variability and function of the long terminal repeat (LTR) from syncytium-inducing (SI) and non-syncytium-inducing (NSI) HIV-1. Twenty LTR DNA clones were obtained by polymerase chain reaction amplification and molecular cloning from short-term cultures of SI and NSI viruses from an AIDS patient and two asymptomatic individuals, respectively. All the LTR clones tested contained multiple nucleotide changes (mostly G-to-A transitions), compared to the subtype B consensus sequence, which were clustered within the negative regulatory element, including NF-AT, USF, and TCF-1 alpha binding sites. The core promoter/TAR region sequences were highly conserved. The basal and Tat-mediated transcriptional activities of selected LTR clones tested were 0.1 to 1 and 0.2 to 0.5 times that of the control, respectively, regardless of the SI or NSI origin of the clones. Phylogenetic analysis revealed interi-solate sequence divergence in the LTR that was similar but not identical to previously analyzed vif sequences from the same samples. In particular, the inter-isolate distances from reference sequences differed for the LTR and vif. This raises the possibility that recombination occurred between corresponding LTR and vif loci of the quasi-species present in the isolates described here.

Acquired Immunodeficiency Syndrome↗
PubMed2006

N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure.

Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the co-occurrence of D30N and L90M. Third, D30N+N88D+L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N-->D30N+N88D-->D30N+N88D+L90M-->D30N+N88D+L90M+(L33F+/-I84V or M46I/L+/-I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.

Base Sequence↗
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↗
PubMed2026

Identification and masking of artifactual and misleading within-host variants in deep-sequencing SARS-CoV-2 data.

Deep-sequencing data are increasingly used to study within-host viral diversity and to inform evolutionary inference. For SARS-CoV-2, analyses based on intra-host single-nucleotide variants (iSNVs) have been widely applied to quantify within-host diversity and infer transmission dynamics. However, these applications critically depend on the reliable identification of low-frequency variants, which remain vulnerable to systematic and technical artifacts. In this study, we show that recurrent artifactual iSNVs are common in large-scale SARS-CoV-2 sequencing data and can persist even under conservative minor allele frequency thresholds. Using data from the UK's Office for National Statistics COVID-19 Infection Survey, we demonstrate that such artifacts are predominantly sequencing center-specific rather than primer-specific. Each center exhibits a modest, distinct set of recurrent artifactual variants showing little overlap with sites routinely masked at the consensus level. To address this, we developed a systematic, dataset-aware framework that uses recurrence within sequencing datasets to identify small, noise-adapted sets of artifactual iSNVs to mask. Applying this framework reduces spurious sharing of low-frequency variants between samples and qualitatively alters downstream inferences, including estimates of within-host diversity and transmission bottleneck sizes. Although this study focused on SARS-CoV-2, it is likely that recurrent artifactual iSNVs will be problematic for other viruses as mass-sequencing becomes increasingly routine. Together, these findings highlight the importance of explicit, dataset-aware artifact control for robust inference from within-host variation, particularly as genomic studies increasingly seek to exploit sub-consensus diversity in rapidly evolving pathogens.

Humans↗
PubMed2003

Estimating the distribution of selection coefficients from phylogenetic data with applications to mitochondrial and viral DNA.

The distribution of selection coefficients of new mutations is of key interest in population genetics. In this paper we explore how codon-based likelihood models can be used to estimate the distribution of selection coefficients of new amino acid replacement mutations from phylogenetic data. To obtain such estimates we assume that all mutations at the same site have the same selection coefficient. We first estimate the distribution of selection coefficients from two large viral data sets under the assumption that the viral population size is the same along all lineages of the phylogeny and that the selection coefficients vary among sites. We then implement several new models in which the lineages of the phylogeny may have different population sizes. We apply the new models to a data set consisting of the coding regions from eight primate mitochondrial genomes. The results suggest that there might be little power to determine the exact shape of the distribution of selection coefficient but that the normal and gamma distributions fit the data significantly better than the exponential distribution.

Algorithms↗