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At least 1,765 records · Page 98Linked to original sources
PubMed2002

Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions.

BACKGROUND: A new HIV-1 treatment strategy based on repeated structured treatment interruptions (STI) is currently being evaluated in clinical trials to determine whether immune cell-mediated control of viral replication can be stimulated by intermittent periods of viral replication. The potential for selection of drug-resistant quasi-species remains a major concern of such a treatment strategy. METHODS: Plasma and peripheral blood lymphocyte (PBL) samples from 12 patients who had three consecutive STIs were studied. Genotypic analysis was based on population and clonal sequencing. Drug susceptibility and their corresponding replication capacities were evaluated by a single-cycle growth assay. RESULTS: Consistent with a loss of phenotypic susceptibility to lamivudine, the M184V mutation was detected by genotypic analysis (direct and clonal sequencing) in plasma samples collected from two patients at the end of the second or third STI. Longitudinal analysis of patient samples revealed a step-wise increase in the M184V mutation in each patient virus population over successive STIs, despite the lower replicative capacity associated with this mutation in the absence of antiviral agents. CONCLUSION: Drug-resistant virus can rise to high frequencies in chronically HIV-1 infected individuals during consecutive STIs. Evolution of resistance is likely to be more important in patients with prior suboptimal therapies, particularly when few mutations are required for resistance. Maximum care should be taken in designing STI protocols that minimize development of drug-resistant mutations that may lead to treatment failure. Thus, drug-resistance testing may be useful before restarting treatment during STI studies.

Adult↗
PubMed2006

The greater than twofold cost of integration for retroviruses.

Sexual reproduction, typically conceived of as a puzzling feature of eukaryotes, has posed an extraordinary evolutionary challenge in terms of the twofold replicative advantage of asexual over sexual organisms. Here we show mathematically that a greater than twofold cost is paid by retroviruses such as HIV during reverse transcription. For a retrovirus, replication is achieved through RNA reverse transcription and the effectively linear growth processes of DNA transcription during gene expression. Retroviruses are unique among viruses in that they show an alternation of generations between a diploid free living phase and a haploid integrated phase. Retroviruses engage in extensive recombination during the synthesis of the haploid DNA provirus. Whereas reverse transcription generates large amounts of sequence variation, DNA transcription is a high-fidelity process. Retroviruses come under strong selection pressures from immune systems to generate escape mutants, and reverse transcription into the haploid DNA phase serves to generate diversity followed by a phase of transcriptional clonal expansion during the restoration of diploidy from a stable, long lived, DNA encoded provirus.

Animals↗
PubMed1997

Three major alleles of rotavirus NSP4 proteins identified by sequence analysis.

Comparison of nonstructural glycoprotein NSP4 gene sequences from 22 rotavirus strains originating from six host species and of 14 different combinations of G and P types revealed the presence of three distinct NSP4 alleles, represented by strains Wa, KUN and AU-1. Genetic distances between any of these alleles (18.0%) were significantly greater than those within each allele (5.5%) and phylogenetic analysis suggested that divergence into three distinct alleles had occurred at about the same time during evolution. While amino acid variation among strains was minimal in the amino-terminal two-thirds of the protein (aa 1-130), variability increased toward the carboxy terminus of the enterotoxic peptide region (aa 114-135) and was greatest between residues 135 and 141. Comparison of the amino acid sequences corresponding to the enterotoxic peptide region between strains isolated from asymptomatic neonates and those from children with diarrhoea failed to identify any conserved changes that correlated with the capacity of the virus to cause disease. Amino acids were relatively conserved in the domains important for viral morphogenesis.

Alleles↗
PubMed2004

Phylogenetic analysis of a human group B rotavirus WH-1 detected in China in 2002.

A human group B rotavirus strain WH-1 was detected in an adult sporadic case of diarrhea in Wuhan, China in 2002. In this study, the gene sequences of WH-1 were determined in order to examine the phylogenetic relatedness to other human group B rotaviruses found previously in China (ADRV, in 1982), India (CAL-1, in 1998), and Bangladesh (Bang373, in 2000), as well as animal viruses, and to estimate the mutation rate of group B rotavirus. VP7 (major outer capsid protein) gene of WH-1 showed extremely high sequence identity (98.6%) to ADRV and showed relatively high sequence identities to CAL-1 (92.5%) and Bang373 (92.4%). In contrast, identities to animal (bovine and murine) group B rotaviruses were considerably lower (61-64%). Other gene segments of WH-1 encoding VP2, VP4, VP6, NSP1-NSP3, and NSP5 also showed high sequence identities to ADRV genes (98-99%), which were generally higher than those to CAL-1 genes and Bang373 genes (90-95%). However, amino acid sequence identities between WH-1 and ADRV were almost the same (VP2, VP6, and NSP3), or lower (NSP2) than those between WH-1 and CAL-1 (or Bang373). Since rates of synonymous substitution and transition between WH-1 and ADRV were similar for all the segments analyzed, genetic evolution was considered to have occurred neutrally and at a similar speed in most of the RNA segments. Based on the sequence divergence between WH-1 and ADRV, the mutation rate in natural condition of human group B rotavirus was estimated as 7.9 x 10(-4) substitution/site per year. The frequency of synonymous substitution between ADRV and Bang373 was 5.7 times higher than that between ADRV and WH-1, suggesting that the group B rotaviruses of Indian-Bangladeshi lineage diverged from that of Chinese lineage several decades ago.

Adult↗
PubMed1984

Opportunities for study of lymphoid neoplasia in Africa.

Animal models have strongly suggested that lymphoid leukaemias and malignant lymphomas might have a viral etiology. Following the first report by Ludwig Gross in 1951 of the transmission of mouse leukaemia by cell-free filtrates inoculated into newborn mice and the subsequent identification of many tumour-inducing type-C viruses in animals, attention was focused on the RNA retroviruses. However, it was work in Africa which led to the recognition of Burkitt's lymphoma as an entity and to the discovery of the Epstein-Barr virus. Many refer to this DNA virus as the first recognized human tumour virus. The research that these early studies stimulated has resulted in enormous progress in our understanding of human carcinogenesis and in highly significant advances in therapy. More recently, the first human retrovirus was identified and characterized in the laboratory of Dr Robert Gallo. There is increasing evidence that this virus, isolated from a patient with a T-cell lymphoma, is etiologically associated with a specific type of T-cell neoplasm first described in Japan. Africa may be considered the cradle of geographical pathology and the potential for generating unique information on cancer etiology and cancer control is still enormous. Lymphoid neoplasms are excellent models for the study of human cancer, particularly in Africa, since as tumours of the immune system, their induction and evolution is strongly influenced by those environmental factors, such as infection and nutrition, which have a profound effect on the immune response. In addition, there is good evidence that at least some of the tumours in this group are associated with specific transforming viruses. There is an immediate need to collect accurate, reproducible and comparable data on the incidence and characteristics of the different types of lymphoid neoplasia and on the populations in which they occur in the various African countries. Such data will provide the basis for undertaking simultaneous or subsequent etiological and therapeutic studies. Realistic approaches to these goals are considered and specific studies relating to questions posed by available information discussed.

Adolescent↗
PubMedDate not supplied

Molecular epidemiology of polioviruses.

Poliovirus isolates can be identified according to their genotypes with use of the technique of oligonucleotide fingerprinting. Fingerprint analysis is performed by cleaving the viral RNA genome with ribonuclease T1 and separating the fragments (oligonucleotides) in two dimensions. The larger, structurally unique oligonucleotides distribute into patterns ("fingerprints") highly characteristic of a specific overall RNA sequence. Isolates from the same epidemic have very similar fingerprints. Isolates from distinct epidemics have very different fingerprints, a consequence of the rapid evolution of polioviruses during replication in humans. Similarity in the fingerprints of case isolates provides independent evidence for epidemiologic linkage. Fingerprinting can readily distinguish vaccine-related isolates from wild strains. Contemporary vaccine-related isolates are very probably vaccine-derived because their fingerprints contain characteristic vaccine-strain oligonucleotide spots (types 1 and 3) and because their wild-type parents are unlikely to have survived largely unaltered in the natural environment. Some examples of applications of this technique within different epidemiologic settings are described.

Humans↗
PubMed2003

Therapy with interferon-alpha plus ribavirin for membranoproliferative glomerulonephritis induced by hepatitis C virus.

We describe a treatment made with interferon-alpha (IFN-alpha) plus ribavirin of two patients with membranoproliferative glomerulonephritis (MPGN) induced by hepatitis C virus (HCV): case # 1 was a 22-yr-old woman with leg and facial edema, hypertension and proteinuria, whose liver biopsy revealed chronic active hepatitis; and case # 2 was a 42-yr-old man with anasarca, hypertension and proteinuria, whose liver biopsy indicated cirrhosis. Both had anti-HCV, HCV-RNA and cryoglobulins. IFN-alpha (3 million units (MU), 3 times/week) and ribavirin (1 g/day) were administered for 12 months. The drugs were well tolerated by both patients. Serum alanine aminotransferase (ALT) levels normalized and HCV-RNA became negative. Cryoglobulins disappeared and an improvement in renal disease was seen after 6 months of therapy. However, after 9 months, case # 2 presented ALT elevation, and proteinuria was detected. Two years after the end of therapy, both patients were negative in repeated HCV-RNA and cryoglobulin tests. Case # 1 was asymptomatic, with normal liver and renal tests, and case # 2 had normal blood pressure, with mild edema of the ankles. Based on the evolution of these two cases, the association of IFN-alpha and ribavirin may be a therapeutic option for patients with MPGN related to HCV.

Adult↗
PubMed1997

Comparison of HCV RNA assays for the detection and quantification of hepatitis C virus RNA levels in serum of patients with chronic hepatitis C treated with interferon.

Detection and quantification of hepatitis C virus (HCV) RNA levels by using the standardized qualitative Amplicor HCV and quantitative Amplicor HCV Monitor assays (Roche Molecular Systems) were evaluated in 48 patients with chronic hepatitis C treated with interferon. Results were compared with an in-house reverse transcription and polymerase chain reaction (RT-PCR) assay and the branched DNA (bDNA) assay (Quantiplex, version 1.0, Chiron Diagnostics). Concordance of the qualitative results with the Amplicor HCV and in-house RT-PCR assays occurred in 82% of the samples. All but one of the discrepant specimens were found positive by the Amplicor HCV assay and negative by the in-house RT-PCR. Among the samples with HCV RNA levels measurable with the Amplicor HCV Monitor assay, 22% had HCV RNA titers below the detection limit of the Quantiplex assay. A statistically significant correlation was found between the 2 quantitative assays, although lower titers were obtained with the Amplicor HCV Monitor assay. More important, a good correlation was observed in the evolution of viremia as measured by the 2 assays during interferon therapy. During follow-up of interferon treatments, with the Amplicor HCV Monitor assay, persisting viremia was still detected in 27% of the patients who normalised alanine aminotransferase (ALT), emphasizing the bioclinical relevance of the assay. Pre-treatment serum HCV RNA levels above 10(5) copies/ml were found more frequently in nonresponders than in responders (76% vs. 44%; P < 0.05). Given their great sensitivity and the significant correlations, the Amplicor HCV qualitative and quantitative assays appear useful for the diagnosis and management of hepatitis C infection, and especially for monitoring of therapy.

Adult↗
PubMed1999

Phylogenetic analysis of a highly conserved region of the polymerase gene from 11 coronaviruses and development of a consensus polymerase chain reaction assay.

Viruses in the genus Coronavirus are currently placed in three groups based on antigenic cross-reactivity and sequence analysis of structural protein genes. Consensus polymerase chain reaction (PCR) primers were used to obtain cDNA, then cloned and sequenced a highly conserved 922 nucleotide region in open reading frame (ORF) 1b of the polymerase (pol) gene from eight coronaviruses. These sequences were compared with published sequences for three additional coronaviruses. In this comparison, it was found that nucleotide substitution frequencies (per 100 nucleotides) varied from 46.40 to 50.13 when viruses were compared among the traditional coronavirus groups and, with one exception (the human coronavirus (HCV) 229E), varied from 2.54 to 15.89 when compared within these groups. (The substitution frequency for 229E, as compared to other members of the same group, varied from 35.37 to 35.72.) Phylogenetic analysis of these pol gene sequences resulted in groupings which correspond closely with the previously described groupings, including recent data which places the two avian coronaviruses--infectious bronchitis virus (IBV) of chickens and turkey coronavirus (TCV)--in the same group [Guy, J.S., Barnes, H.J., Smith L.G., Breslin, J., 1997. Avian Dis. 41:583-590]. A single pair of degenerate primers was identified which amplify a 251 bp region from coronaviruses of all three groups using the same reaction conditions. This consensus PCR assay for the genus Coronavirus may be useful in identifying as yet unknown coronaviruses.

Amino Acid Sequence↗
PubMed1997

Long-term evolution of the 5'UTR and a region of NS4 containing a CTL epitope of hepatitis C virus in two haemophilic patients.

Haemophilic patients exposed to unsterilized clotting factor concentrates prior to 1985 have become infected with hepatitis C virus (HCV). We have studied the sequence evolution of the 5'UTR and a region of NS4 over 12 years in one human immunodeficiency virus (HIV) positive haemophilic patient and 14 years for one HIV negative haemophilic patient. One sample each year from the date of HCV infection to 1994 was analysed for genotype, virus load and nucleotide sequence of the two genetic loci. Both patients were infected with HCV genotype 1 throughout the study period. The virus load profiles were similar except that the profile for the HIV infected patient was displaced 4 years earlier relative to the other patient. Mean divergence of the quasispecies at both the 5'UTR and NS4 loci was higher in the HIV coinfected patient. Phylogenetic analysis indicated that evolution of the 5'UTR was host independent, whereas the NS4 region containing a CD8 restricted CTL epitope evolved in a host specific fashion.

Amino Acid Sequence↗
PubMed1976

Comparisons of the immunological properties of two structural polypeptides of type C RNA viruses endogenous to old world monkeys.

Immunologically very closely related type C RNA viruses are endogenous to the domestic cat and to an old world primate, the baboon. In the present studies, radioimmunological techniques have been developed for detection of the 15,000 and 30,000 molecular weight (MW) polypeptides of each virus. The much more pronounced type-specific antigenic determinants of the lower MW polypeptides made it possible to readily differentiate these viruses from each other as well as from a type C virus isolate from a second baboon species. Normal rhesus monkey tissues were partially purified and shown to contain a reactivity with MW and immunological properties similar to that of the baboon virus 30,000 MW polypeptide. Despite a similar degree of purification, antigenic reactivity like that of the baboon virus 15,000 MW polypeptide was undetectable even in the brodest immunological tests available for this polypeptide. The present findings indicate that the immunological properties of two structural polypeptides of closely related viruses endogenous to primate and feline species have undergone different rates of antigenic change in the course of evolution within their respective host cell genome.

Animals↗
PubMed1997

[Variation in hepatitis C virus NS 5b nucleotide sequence and its relationship with interferon treatment].

In order to investigate variation in hepatitis C virus (HCV) nonstructural 5b (NS5b) nucleotide sequence and the relationship with interferon treatment, cDNA containing in this region were obtained by reverse transcription-polymerase chain reaction from the sera of 4 HCV RNA positive asymptomatic chronic carriers and 9 chronic hepatitis C patients. The cDNA were then directly analysed by polymerase-chain-reaction-directed sequencing. Compared with three published HCV type II/1b sequences (HCV-J, HC-C2 and HCV-BDS), the homology of HCV was lower in the patients with chronic hepatitis C (93.52% +/- 2.09% average), especially in nonresponders to interferon (92.70 +/- 1.90% average), than in asymptomatic HCV carriers (95.65 +/- 2.61%). In 5 patients, HCV RNA was eliminated by interferon treatment. In the remaining 4 interferon-treated HCV survived patients there were 9-48 nucleotide substitutions in HCV mutants out of 380 nucleotides, resulting 6-20 amino acids changes out of 126 amino acids. These results suggested that NS5b region variants play an important role in maintaining persistent infection and the evolution of NS5b is associated with the effect of interferon treatment.

Adult↗
PubMed1993

Sequence comparison and mutational analysis of elements that may be involved in the regulation of DNA synthesis in HIV-1.

The large number of sequenced clones of HIV-1 and related viruses made it possible to indicate conserved elements with potential regulatory or structural functions. Such analysis was combined with directed mutagenesis in order to investigate the importance of elements that may influence the initiation of plus-strand DNA synthesis. The main site for plus-strand initiation is a polypurine tract near the 3' end of the viral RNA (the 3' PPT). An exact copy of this PPT is located in the middle of the genome (the internal PPT). Upstream from the internal PPT there is an inverted repeat. Mutants designed to upset the internal PPT (i.e., purine to pyrimidine changes), as well as mutants designed to abolish the potential stem-loop formation (changes around the internal PPT or in the upstream inverted repeat) both resulted in viruses with a reduced ability to replicate. Upsetting the stem-loop formation was, however, less harmful than changing the polypurine nature of the PPT. Changing a conserved T on the 3' side of the PPT to a C did not affect the phenotype.

Base Sequence↗
PubMed2002

Molecular indetermination in the transition to error catastrophe: systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity.

Studies with several RNA viruses have shown that enhanced mutagenesis resulted in decreases of infectivity or virus extinction, as predicted from virus entry into error catastrophe. Here we report that lymphocytic choriomeningitis virus, the prototype arenavirus, is extremely susceptible to extinction mutagenesis by the base analog 5-fluorouracil. Virus elimination was preceded by increases in complexity of the mutant spectra of treated populations. However, careful molecular comparison of the mutant spectra of several genomic segments suggests that the largest increases in mutation frequency do not predict virus extinction. Highly mutated viral genomes have escaped detection presumably because lymphocytic choriomeningitis virus replicates at or near the error threshold, and genomes in the transition toward error catastrophe may have an extremely short half-life and escape detection with state-of-the-art cloning and sequencing technologies.

Animals↗
PubMed1985

Structure and evolution of two related transcription units of Epstein-Barr virus carrying small tandem repeats.

Two regions of the Epstein-Barr virus (EBV) genome carrying partially homologous clusters of short tandem repeats (NotI and PstI repeats) flanked by 1044 and 1045 base pairs with almost complete homology (DL and DR, left and right duplication, respectively) were most abundantly transcribed into poly(A)+ mRNA after induction with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. The nucleotide sequence of both repeat clusters and the conserved upstream regulatory sequences from the M-ABA EBV strain are presented. Nearly the whole part of the sequences coding for the RNAs is covered by the NotI and PstI repeats, respectively. The regulatory sequences for these genes are located in the homologous regions of 1044 and 1045 base pairs (DL and DR, respectively). A CAAT box, a TATA box, and other herpes simplex virus-like elements were identified for both transcription units. The initiation points and the 3' ends of both inducible RNAs were mapped by S1 nuclease analysis. Both genes have open reading frames and may potentially code for proteins with repetitive amino acid compositions. The structure of these two inducible EBV genes is discussed, and an evolutionary model is proposed for the generation of gene duplication in the M-ABA strain of EBV.

Biological Evolution↗
PubMed2001

Structure of the human zinc finger protein HIVEP3: molecular cloning, expression, exon-intron structure, and comparison with paralogous genes HIVEP1 and HIVEP2.

Here we report the cloning and characterization of HIVEP3, the newest member in the human immunodeficiency virus type 1 enhancer-binding protein family that encodes large zinc finger proteins and regulates transcription via the kappaB enhancer motif. The largest open reading frame of HIVEP3 contains 2406 aa. and is approximately 80% identical to the mouse counterpart. The HIVEP3 gene is located in the chromosomal region 1p34 and is at least 300 kb with 10 exons. RNA studies show that multiple HIVEP3 transcripts are differentially expressed and regulated. Additionally, transcription termination occurs in the ultimate exon, exon 10, or in exon 6. Therefore, HIVEP3 may produce protein isoforms that contain or exclude the carboxyl DNA binding domain and the leucine zipper by alternative RNA splicing and differential polyadenylation. Sequence homologous to HIVEP3 exon 6 is not found in mouse nor are the paralogous genes HIVEP1 and HIVEP2. Zoo-blot analysis suggests that sequences homologous to the human exon 6 are present only in primates and cow. Therefore, a foreign DNA harboring a termination exon likely was inserted into the HIVEP3 locus relatively recently in evolution, resulting in the acquisition of novel gene regulatory mechanisms as well as the generation of structural and functional diversity.

Amino Acid Sequence↗
PubMed1993

A general method for the identification of transcribed retrovirus sequences (R-U5 PCR) reveals the expression of the human endogenous retrovirus loci HERV-H and HERV-K in teratocarcinoma cells.

During the past decade, different types of endogenous retroviral sequences have been defined in the human genome usually by low stringency hybridization employing DNA probes of evolutionary conserved animal retrovirus genes. Although all human genomic loci sequenced were found to be defective or interspersed with stop codons, indirect evidence is accumulating that human endogenous retroviral loci are expressed at least in some instances. One example is the synthesis of retroviral particles in human teratocarcinoma cell lines observed by electron microscopy. To establish a link between virus expression and genomic loci we searched for retroviral RNA in human cellular mRNA populations using a generally applicable method. A tRNA-derived primer complementary to a putative retroviral primer binding site was extended by reverse transcription and this product was elongated with a homopolymeric stretch and amplified by PCR (R-U5 PCR). Cloning and sequencing of such products revealed that the endogenous retroviral loci HERV-H and HERV-K are expressed in those human teratocarcinoma cell lines which produce retroviral particles. The size distribution of four HERV-K mRNAs detected in Northern blots is reminiscent of the complex expression pattern seen with a number of exogenous retroviruses.

Animals↗
PubMed1996

Emerging and reemerging of filoviruses.

Filoviruses are causative agents of a hemorrhagic fever in man with mortalities ranging from 22 to 88%. They are enveloped, nonsegmented negative-stranded RNA viruses and are separated into two types, Marburg and Ebola, which can be serologically, biochemically and genetically distinguished. In general, there is little genetic variability among viruses belonging to the Marburg type. The Ebola type, however, is subdivided into at least three distinct subtypes. Marburg virus was first isolated during an outbreak in Europe in 1967. Ebola virus emerged in 1976 as the causative agent of two simultaneous outbreaks in southern Sudan and northern Zaire. The reemergence of Ebola, subtype Zaire, in Kikwit 1995 caused a worldwide sensation, since it struck after a sensibilization on the danger of Ebola virus disease. Person-to-person transmission by intimate contact is the main route of infection, but transmission by droplets and small aerosols among infected individuals is discussed. The natural reservoir for filoviruses remains a mystery. Filoviruses are prime examples for emerging pathogens. Factors that may be involved in emergence are international commerce and travel, limited experience in diagnosis and case management, import of nonhuman primates, and the potential of filoviruses for rapid evolution.

Animals↗