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PubMed2002

Incident hepatitis C virus infection in a community-based population in Japan.

Hepatitis C virus (HCV) is an important cause of liver disease throughout the world. However, the natural history and pathogenesis of this infection is still not completely understood. The aim of this study was to characterize the evolution of incident, asymptomatic HCV infection in a community-based population in Japan. The Miyazaki Cohort Study is a prospective study of adult residents in two villages, one of which has a very high prevalence of HCV. Nine hundred and seventy-three people from this village were enrolled in the cohort between 1984 and 1995, with antibodies to HCV (anti-HCV) found in 23%. During subsequent visits to annual health screens, new HCV seroconverters were identified among susceptible individuals, and their sequential samples were tested for anti-HCV, HCV-RNA, and HCV core antigen. Fourteen participants (six males, eight females) acquired anti-HCV during the first 11 years of study follow-up, at an incidence rate of 362 per 100 000 person-years. Detectable HCV-RNA and high anti-HCV titres (> 1:2048) were observed for more than 5 years following seroconversion in 80% (8/10) of seroconverters with sufficient information, indicating the development of persistent infection in these subjects. Three (37.5%) of the eight sero converters with persistent infection had fairly consistent, albeit mild, alanine aminotransferase elevations (30-130 IU/L) during the study. Anti-HCV seroconversions occurred at a very high rate in this community-based population in Japan, in which this infection is endemic. Persistence also developed at a high frequency among the cases of newly acquired infection, although the associated liver enzyme abnormalities were mild.

Adult↗
PubMed1999

Emergence and genetic evolution of HIV-1 variants with mutations conferring resistance to multiple reverse transcriptase and protease inhibitors.

The emergence of genotypic resistance in protease and reverse transcriptase (RT) gene regions was longitudinally evaluated in plasma samples from a group of 12 HIV-1-infected patients treated with different combination of antiretroviral therapies and selected on the basis of their clinical failure. Complex mutational patterns in the reverse transcriptase gene were observed. In particular, combinations of AZT (41L, 67N, 70R, 210W, and 219Q/E) and 3TC (184M) were seen in 10 patients. Two patients presented codon 151 multinucleoside analogue resistance (MNR). Additionally, seven patients harbored RT nonnucleoside analogue-related resistance substitutions (98G, 103N, and 181C). Multiple protease-selected mutations were found in each patient with an average of six substitutions per patient, with 10I/F/V, 63P, 71V, 82A/T, 84V, and 90M being the most prevalent substitutions. Overall, these results showed that for most patients virological failure was coupled with detectable genotypic resistance. Furthermore, most patients exhibited genotypic resistance to almost all available anti-HIV-1 drugs. The high viral loads found in most patients at the end of the study suggest that the replication of these multidrug resistant viruses are not severely compromised. Phylogenetic analysis of these pol sequences revealed that a specific HIV-1 genotype prone to develop multidrug resistance was not found.

Adult↗
PubMed2002

Differential selection of specific human immunodeficiency virus type 1/JC499 variants after mucosal and parenteral inoculation of chimpanzees.

Regardless of the route of transmission, it is generally accepted that the human immunodeficiency virus type 1 (HIV-1) quasispecies transmitted from an infected individual to an uninfected individual is genetically homogeneous. This finding and the observation that HIV-1 genotypes in recipients are minor variants in the donors suggest strongly that selection for specific variants occurs. However, most analyses have been limited to the V3 region of env. In addition, the exact time at which most new infections occurred was not known, making it almost impossible to analyze virus populations present in donor-recipient pairs at the time of HIV-1 transmission. To circumvent this problem, three chimpanzees were inoculated with a genetically defined stock of cell-free HIV-1/JC499 by one of three routes: intravenously or via the cervical or penile mucosa. PCR products of the C2-to-V5 region of env were amplified from both proviral DNA and virion RNA in blood samples collected soon after infection and were screened by heteroduplex analysis (HDA). Those PCR products with distinct HDA banding patterns were cloned and sequenced. In all three animals, transmitted variants encoded one of two V3-loop populations identified in the inoculum, indicating relative homogeneity in this region. However, different virus populations, defined by combinations of specific V4 and V5 sequences, were found when variants in the animal inoculated intravenously (at least 13 V4-plus-V5 combinations) were compared with those in the two animals inoculated by the mucosal routes (limited to only four V4-plus-V5 combinations). The only V4-plus-V5 population in variants found in all three chimpanzees was the major population in the inoculum, which contained viruses with more than 30 different V4-plus-V5 combinations. That the majority of the V4-plus-V5 genotypes in variants transmitted to all three animals were minor populations in the inoculum indicated that selective transmission defined by the V4-plus-V5 regions had occurred but that distinct populations were transmitted by parenteral versus mucosal routes. These results indicate that the putative homogeneity of HIV-1 variants in a newly infected individual might be an artifact of the region of the env gene evaluated and that regions other than V3 might play a major role in selective transmission.

Amino Acid Sequence↗
PubMed2000

In vitro selection of novel RNA ligands that bind human cytomegalovirus and block viral infection.

Ribonuclease-resistant RNA molecules that bind to infectious human cytomegalovirus (HCMV) were isolated in vitro from a pool of randomized sequences after 16 cycles of selection and amplification. The two ligands (L13 and L19) characterized exhibited high HCMV-binding affinity in vitro and effectively inhibited viral infection in tissue culture. Their antiviral activity was also specific as they only reacted with two different strains of HCMV but not with the related herpes simplex virus 1 and human cells. These two ligands appeared to function as antivirals by blocking viral entry. Ultraviolet (UV) crosslinking studies suggested that L13 and L19 bind to HCMV essential glycoproteins B and H, respectively. Thus, RNA ligands that bind to different surface antigens of HCMV can be simultaneously isolated by the selection procedure. Our study demonstrates the feasibility of using these RNA ligands as a research tool to identify viral proteins required for infectivity and as an antiviral agent to block viral infection.

Antiviral Agents↗
PubMed1984

Complete nucleotide sequence of the mRNA coding for the N protein of vesicular stomatitis virus (New Jersey serotype).

The nucleotide sequence of the mRNA encoding the nucleocapsid protein of the New Jersey serotype (Ogden strain) of vesicular stomatitis virus (VSV) was determined from two overlapping cDNA clones spanning almost entirely the coding region of the mRNA. The 5'-terminal noncoding sequence present in the mRNA but not in the cDNA clones was determined from a primer extended to the 5' terminus of the mRNA. The mRNA is 1329 nucleotides long (excluding polyadenylic acid) and encodes a protein of 422 amino acids. The nucleotide sequence was compared with the previously determined nucleotide sequence of the nucleocapsid protein of the Indiana serotype. An overall identity of 67.7% was found between the two serotypes. The only place where insertions and/or deletions have occurred during the evolution of the two viral genes from their presumed common ancestor is in the untranslated region. The nonidentical nucleotides are distributed throughout the length of the mRNA although not in an entirely random manner. The predicted amino acid sequence demonstrates that both proteins are initiated from the initiator codon located at the same distance from the 5' end (nucleotides 14 to 16) and contain the same number of amino acids. An overall identity of more than 80% of the amino acid sequence was observed between the two proteins when conservative replacements of amino acids were considered.

Amino Acid Sequence↗
PubMed1996

The complete nucleotide sequence and genome organization of barley mild mosaic virus (Na1 strain).

The 5'-terminal half of RNA 1 and whole of RNA 2 of barley mild mosaic bymovirus Na1 strain (BaMMV-Na1) were sequenced to give together with the published data its complete genomic sequence. BaMMV-Na1 RNA 1 and RNA 2 consist of 7263 and 3516 nucleotides, excluding the 3' poly A tails, respectively. RNA 1 encodes a single large polyprotein of 2258 amino acids (M(r) 256K), containing eight putative functional proteins, and RNA 2 also encodes one polyprotein of 891 amino acids (M(r) 98K), containing two functional proteins. These functional proteins are arranged in the same manner as in RNA 1 and RNA 2 of barley yellow mosaic bymovirus (BaYMV), and significant amino acid sequence homology (25-58%) exists between the proteins of the two viruses. The BaMMV-Na1 proteins show less amino acid sequence homology (18-32%) with the corresponding proteins of potyviruses or rymoviruses than with those of BaYMV. Comparisons of the BaMMV-Na1 proteins with the corresponding proteins of other partially sequenced BaMMV isolates show 87-98% amino acid sequence identity. There is 91-94% nucleotide sequence identity between the 3' non-coding regions (NCRs) in RNA 1 or RNA 2 of BaMMV-Na1 and other BaMMV isolates, but only 68-72% identity between the 5' NCRs in RNA 2 of BaMMV-Na1 and other BaMMV isolates.

Amino Acid Sequence↗
PubMed2003

Translational control by the 3'-UTR: the ends specify the means.

In most cases, translational control mechanisms result from the interaction of RNA-binding proteins with 5'- or 3'-untranslated regions (UTRs) of mRNA. In organisms ranging from viruses to humans, protein-mediated interactions between transcript termini result in the formation of an RNA loop. Such RNA 'circularization' is thought to increase translational efficiency and, in addition, permits regulation by novel mechanisms, particularly 3'-UTR-mediated translational control. Two general mechanisms of translational inhibition by 3'-UTR-binding proteins have been proposed, one in which mRNA closure is disrupted and another in which mRNA closure is required. Experimental evidence for the latter is provided by studies of interferon-gamma-mediated translational silencing of ceruloplasmin expression in monocytic cells. A multi-species analysis has shown that, in most vertebrates, 3'-UTRs are substantially longer than their 5' counterparts, indicating a significant potential for regulation. In addition, the average length of 3'-UTR sequences has increased during evolution, suggesting that their utilization might contribute to organism complexity.

3' Untranslated Regions↗
PubMed2004

Drift increases the advantage of sex in RNA bacteriophage Phi6.

The pervasiveness of sex and recombination remains one of the most enigmatic problems in evolutionary biology. According to many theoretical models, recombination can increase the rate of adaptation by restoring genetic variation. However, the potential for genetic drift to generate conditions that produce this outcome has yet to be studied experimentally. We have designed and performed an experiment that reveals the effects of drift on existing genetic variation by minimizing the influence of variation on beneficial mutation rate. Our experiment was conducted in populations of RNA bacteriophage Phi6 initiated from a common source population at varying bottleneck sizes. The segmented genome of this virus results in genetic exchange between viruses that co-infect the same host cell. In response to selection for growth in a high-temperature environment, sexual lines outperformed their asexual counterparts on average. The advantage of sex attenuated with increasing effective population size, implying that the rate of adaptation was limited by clonal interference among segments caused by drift. This is the first empirical evidence that the advantage of sex during adaptation increases with the intensity of drift.

Bacteriophage phi 6↗
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↗
PubMed2004

Regulation of RNA function by aminoacylation and editing?

The chemical modification of nucleic acids is a ubiquitous phenomenon. Aminoacylation of tRNAs by aminoacyl-tRNA synthetases (ARSs) is a reaction essentially devoted to protein synthesis but it is used also as an emergency mechanism to recycle stalled ribosomes, and it is required for genome replication in some RNA viruses. In several aminoacyl-tRNA synthetases a correction mechanism known as editing is present to prevent aminoacylation errors. Genome data reveal a growing number of open reading frames encoding ARS-like proteins. This strongly suggests the existence of a widespread and nonconventional machinery for aminoacylation and editing. Here we review the different biological functions of aminoacylation and editing; also we propose an evolutionary scenario for the origin of these two reactions, and hypothesize an extant role for RNA charging and editing outside the genetic code.

Amino Acyl-tRNA Synthetases↗
PubMed2003

Evidence for interspecies transmission of viruses in natural populations of filamentous fungi in the genus Cryphonectria.

Interspecies transmission is a significant evolutionary event that has allowed a variety of pathogens to invade new host species. We investigated interspecies transmission of viruses between the chestnut blight fungus, Cryphonectria parasitica, and a sympatric unidentified Cryphonectria species in Japan. Two isolates of Cryphonectria sp. were found to contain Cryphonectria hypovirus 1 (CHV-1), which has been typically found in C. parasitica. Three lines of evidence support the hypothesis of interspecies transmission of CHV-1. First, host species occur sympatrically and therefore have the opportunity to come into physical contact. Second, we transmitted CHV-1 between species experimentally in the laboratory. Third, phylogenetic analysis of 476 bp of the ORF B region of CHV-1 showed that sequences from Cryphonectria sp. were more closely related to those from C. parasitica than to each other. Local geographical subdivision of virus sequences from both host species argues against the alternative hypothesis of independent evolution of CHV-1 since speciation of their hosts. Based on these findings, we rule out the hypotheses that CHV-1 diverged from viruses in a common ancestor of the hosts, or that ancestral polymorphisms in CHV-1 persisted in the two host taxa. Estimating the direction and frequency of interspecies transmission in nature will require more extensive samples of CHV-1 from both host species.

Ascomycota↗
PubMed2004

Hepatitis C virus mutation affects proteasomal epitope processing.

The high incidence of hepatitis C virus (HCV) persistence raises the question of how HCV interferes with host immune responses. Studying a single-source HCV outbreak, we identified an HCV mutation that impaired correct carboxyterminal cleavage of an immunodominant HLA-A2-restricted CD8 cell epitope that is frequently recognized by recovered patients. The mutation, a conservative HCV nonstructural protein 3 (NS3) tyrosine to phenylalanine substitution, was absent in 54 clones of the infectious source, but present in 15/21 (71%) HLA-A2-positive and in 11/24 (46%) HLA-A2-negative patients with chronic hepatitis C. In order to analyze whether the mutation affected the processing of the HLA-A2-restricted CD8 cell epitope, mutant and wild-type NS3 polypeptides were digested in vitro with 20S constitutive proteasomes and with immunoproteasomes. The presence of the mutation resulted in impaired carboxyterminal cleavage of the epitope. In order to analyze whether impaired epitope processing affected T cell priming in vivo, HLA-A2-transgenic mice were infected with vaccinia viruses encoding either wild-type or mutant HCV NS3. The mutant induced fewer epitope-specific, IFN-gamma;-producing and fewer tetramer(+) cells than the wild type. These data demonstrate how a conservative mutation in the flanking region of an HCV epitope impairs the induction of epitope-specific CD8(+) T cells and reveal a mechanism that may contribute to viral sequence evolution in infected patients.

Amino Acid Sequence↗
PubMed2003

Viremia control despite escape from a rapid and potent autologous neutralizing antibody response after therapy cessation in an HIV-1-infected individual.

The neutralizing Ab response after primary HIV-1 infection is delayed relative to the virus-specific CD8(+) T cell response and the initial decline in plasma viremia. Because nearly all HIV-1 infections result in AIDS, it would be instructive to study cases where neutralizing Ab production commenced sooner. This was done in subject AC10, an individual treated during early infection and in whom a rapid autologous neutralizing Ab response was detected after therapy cessation as rebound viremia declined and remained below 1000 RNA copies/ml of blood for over 2.5 years. This subject's Abs were capable of reducing the infectivity of his rebound virus by >4 logs in vitro at a time when rebound viremia was down-regulated and virus-specific CD8(+) T cells were minimal, suggesting that neutralizing Abs played an important role in the early control of viremia. The rebound virus did not exhibit an unusual phenotype that might explain its high sensitivity to neutralization by autologous sera. Neutralization escape occurred within 75 days and was proceeded by neutralizing Ab production to the escape variant and subsequent escape. Notably, escape was not associated with a significant rise in plasma viremia, perhaps due to increasing CD8(+) T cell responses. Sequence analysis of gp160 revealed a growing number of mutations over time, suggesting ongoing viral evolution in the face of potent antiviral immune responses. We postulate that an early effective neutralizing Ab response can provide long-term clinical benefits despite neutralization escape.

Adult↗
PubMed2002

Codon and amino acid usage in retroviral genomes is consistent with virus-specific nucleotide pressure.

Retroviral RNA genomes are known to have a biased nucleotide composition. For instance, the plus-strand RNA of human immunodeficiency virus (HIV) is A-rich, and the genome of human T cell leukemia virus (HTLV) is C-rich, and other retroviruses have a U-rich or G-rich genome. The biased composition of these genomes is most likely caused by directional mutational pressure of the respective reverse transcriptase enzymes. Using a set of retroviral genomes with a distinct nucleotide composition, we performed skew analyses of the nucleotide bias along the complete viral genome. Distinct nucleotide signatures were apparent, and these typical patterns were generally conserved across the viral genome. Furthermore, it is demonstrated that this typical nucleotide bias, combined with a profound discrimination against the CpG dinucleotide sequence, strongly influences the codon usage of the retroviruses in a direct manner, and their amino acid usage in an indirect manner. The fact that both codon usage and amino acid usage are so closely entwined with the genome composition has important practical implications. For instance, the typical trends in nucleotide usage could influence the molecular phylogenetic reconstruction of the family Retroviridae.

Amino Acids↗
PubMed1998

Evolution of the immune response in the central nervous system following infection with Borna disease virus.

Borna disease virus infection of Lewis rats results in an immune-mediated disease associated with transient meningoencephalitis and persistent viral infection. In the acute phase of disease, perivascular immune cell infiltrates consisted of CD4 + and CD8 + T cells, macrophages and NK cells with peak expression of mRNAs encoding the cytokines IL1alpha, IL2, IL6, TNFalpha, and IFNgamma. In the chronic phase of disease, numbers of NK cells, B cells and activated microglia increased in the brain parenchyma with peak expression of IL4 mRNA. These data were consistent with a switch from a Th1-like, cellular immune response to a Th2-like, humoral immune response.

Animals↗
PubMed1997

Absence of latent Epstein-Barr virus in cutaneous squamoproliferative lesions after solid organ transplantation.

Recent studies implicate Epstein-Barr virus (EBV) in the pathogenesis of an increasing number of lymphoid and epithelial tumors. EBV-related disorders are particularly prevalent in immunosuppressed patients. The most common neoplasms arising in persons receiving long-term immunosuppressive agents after organ transplantation include non-Hodgkin's lymphomas and skin and lip carcinomas. Because EBV plays a major role in the evolution of post-transplantation lymphoproliferative disorders and was recently identified in a squamous cell carcinoma of the lip in a renal transplant recipient, we examined squamoproliferative lesions of the skin and lips for the presence of latent EBV. Twenty-six paraffin-embedded specimens from 23 different squamoproliferative lesions occurring in 9 solid organ transplant recipients were examined for the presence of latent EBV by in situ hybridization for EBV-encoded small RNA (EBER-1). The squamoproliferative lesions included 16 squamous cell carcinomas, 3 re-excisions of squamous cell carcinomas, 5 basal cell carcinomas, and 2 actinic keratoses. Two lesions from a single patient exhibited clusters of positive dermal lymphocytes after in situ hybridization with the EBER-1 probe. This patient is currently without clinical evidence of a lymphoproliferative disorder 2 years after the first biopsy showing this phenomenon. The squamoproliferative lesions were all uniformly negative. EBV does not seem to play a role in the initiation or progression of the majority of cutaneous squamoproliferative lesions arising in immunosuppressed patients who received solid organ transplants.

Adult↗
PubMed1989

Nucleotide sequence of a neurovirulent variant of the type 2 oral poliovirus vaccine.

Infectious cDNAs of the Sabin type 2 poliovirus vaccine virus and a vaccine-derived neurovirulent type 2 strain (P2/117) have been cloned in Escherichia coli. Nucleotide sequence analysis revealed that P2/117 differs from the vaccine strain by just 23 point mutations. Three occur in the 5' noncoding region. The remainder result in a total of 5 coding changes located in VP1, VP4, 2B, and 3D. The likely role of these mutations in the evolution to neurovirulence is discussed.

Animals↗
PubMed2006

On the origin and functions of RNA-mediated silencing: from protists to man.

Double-stranded RNA has been shown to induce gene silencing in diverse eukaryotes and by a variety of pathways. We have examined the taxonomic distribution and the phylogenetic relationship of key components of the RNA interference (RNAi) machinery in members of five eukaryotic supergroups. On the basis of the parsimony principle, our analyses suggest that a relatively complex RNAi machinery was already present in the last common ancestor of eukaryotes and consisted, at a minimum, of one Argonaute-like polypeptide, one Piwi-like protein, one Dicer, and one RNA-dependent RNA polymerase. As proposed before, the ancestral (but non-essential) role of these components may have been in defense responses against genomic parasites such as transposable elements and viruses. From a mechanistic perspective, the RNAi machinery in the eukaryotic ancestor may have been capable of both small-RNA-guided transcript degradation as well as transcriptional repression, most likely through histone modifications. Both roles appear to be widespread among living eukaryotes and this diversification of function could account for the evolutionary conservation of duplicated Argonaute-Piwi proteins. In contrast, additional RNAi-mediated pathways such as RNA-directed DNA methylation, programmed genome rearrangements, meiotic silencing by unpaired DNA, and miRNA-mediated gene regulation may have evolved independently in specific lineages.

Animals↗