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At least 1,243 records · Page 69Linked to original sources
PubMed1996

Reproducible nonlinear population dynamics and critical points during replicative competitions of RNA virus quasispecies.

RNA virus evolution is generally considered to be highly unpredictable, but tests of determinism in the evolution of competing populations during viral infections have not been performed. Here we study the fate of two closely related evolving quasispecies of vesicular stomatitis virus, by determining the relative concentration of a wild-type clone and a surrogate marked virus subclone (MARM-C) upon extensive competitive replication in a constant cell culture environment. A highly predictable nonlinear behaviour of the two competing populations was found. In addition, the presence of critical points, which are defined as points from which viral competitions may follow different trajectories, has been documented. Critical points were reached after nearly constant periods of time. The dynamics of relative fitness values for both competing populations were calculated during the replication passages. Concomitant with expected fitness gain of both competing viral populations (which follow the Red Queen hypothesis) a tendency for the MARM-C to gain less fitness than the wild-type was observed. Although fitness variations were noisy, this tendency was seen in all evolutionary replicas. Thus, despite the stochastic process of mutation that leads to a continuous generation of mutant genomes during RNA virus replication, a nonlinear, nearly deterministic evolutionary behaviour has been observed. It is proposed that such a behaviour is mediated by a low-pass filter (averaging of mutational noise signals) due to competitive selection among variants.

Analysis of Variance↗
PubMed1995

Polyoma virus middle T antigen: meddler or mimic?

Polyoma virus middle T antigen duplicates the actions of growth-factor receptors in binding the signalling molecules phosphatidylinositol 3'-OH kinase and Shc. These properties indicate that middle T is mitogenic and may be required to overcome inhibition of DNA replication during the lytic life cycle of the virus.

Animals↗
PubMed1986

Ambisense RNA viruses: positive and negative polarities combined in RNA virus genomes.

The coding strategies of arenaviruses (family Arenaviridae) and members of the Phlebovirus genus of the Bunyaviridae differ from those of other negative-sense RNA viruses in that some proteins are coded in viral-complementary RNA sequences and others are coded in the viral RNA sequence. The term ambisense RNA has been proposed to denote these unique coding arrangements. The implications of the ambisense RNA coding strategy for the evolution and infection processes of these viruses are discussed.

Arenaviridae↗
PubMed2026

Viral tags as keys to advancing invasion genomics.

Invasion genetics and genomics have greatly advanced the study of biological invasions, yet they often fail to resolve population dynamics at the fine spatiotemporal scales characteristic of most invasions. We propose shifting the focus away from the higher-order target species towards their viral symbionts, harnessing these as high-resolution 'genetic tags' to overcome many of these limitations. Owing to their comparably smaller genomes, shorter generation times, and higher mutation rates, most viruses evolve on timescales comparable to the invasion dynamics of their higher-order hosts, potentially better proxying and revealing recent dispersal patterns. We present a conceptual framework outlining how virus evolution may shed light on the contemporary spread of their non-native hosts, opening new avenues for invasion genetics, genomics, and management.

Genomics↗
PubMed2026

Transcriptome mining and comparative genomics reveal 36 putative novel marafivirus species and conserved evolution of the marafibox regulatory element.

BACKGROUND: Marafiviruses are plant-infecting RNA viruses associated with several economically important crops, but their genomic diversity remains incompletely characterized. OBJECTIVE: This study aimed to identify previously unrecognized marafivirus genomes and investigate their genomic features and evolutionary relationships. METHODS: Publicly available plant transcriptome datasets were systematically mined to detect marafivirus-like sequences. Recovered genomes were analyzed using comparative sequence analysis, phylogenetic reconstruction, and genome organization characterization. RESULTS: A total of 62 marafivirus-like genomes were recovered from 33 independent sources representing diverse plant hosts. Polyprotein-based comparative and phylogenetic analyses grouped these genomes into 36 lineages likely representing novel species. All newly identified viruses clustered within the Marafivirus clade. Genome organization analysis revealed conserved polyprotein architecture and widespread presence of the marafibox promoter element. Conservation of additional open reading frames among closely related isolates aided identification of potentially functional genes. CONCLUSION: These findings substantially expand the known diversity of marafiviruses and demonstrate the effectiveness of transcriptome mining for discovering previously unrecognized plant viruses.

Phylogeny↗
PubMed2005

Adaptive evolution in perinatal HIV-1.

The immune-viral dynamics of the transmission of HIV-1 from mother to child are poorly understood, despite 20 years of research. Here we review evidence that the maternal immune response against HIV-1 can select forms of the virus that evade immunity and when transmitted have negative consequences in the child. Moreover, recent studies indicate that when wild-type virus is transmitted, an early immune response in the child can lead to the selection of viral escape forms in the first few months of life. These data suggest that adaptive immune surveillance in both mother and child contributes to the pathogenesis of early perinatal HIV-1. These observations augment our general understanding of the processes that determine the evolution of HIV-1 as it passes from one host to another.

Biological Evolution↗
PubMed2002

Virulence and pathogenesis.

Why do viruses cause disease? As intracellular parasites they grow at the expense of the host, yet many infections are non-virulent. We tend to focus on unusual outcomes of infection that are important to the individual but trivial for host-parasite evolution, for example, paralytic polio or viral cancer. The assumption that the features of disease help onward transmission of the virus is true for, say, rabies, but not for AIDS or neurodegenerative diseases. Moreover, minor host differences can result in major changes in pathogen virulence. Although viral burden relates to disease severity, pathogenesis is not necessarily coupled with transmission dynamics.

Animals↗
PubMed1998

Molecular tools for the treatment of hepatitis C.

The treatment of chronic hepatitis C is aimed at eliminating viral replication in order to prevent further evolution towards cirrhosis and hepatocellular carcinoma. Virological parameters include hepatitis C virus (HCV) genotype, qualitative viraemia, quantitative viral load and the characteristics of HCV quasi-species heterogeneity. These parameters can be used to predict and monitor the response to therapy, in order to help clinicians to tailor treatment of chronic hepatitis C and to better understand the molecular mechanisms underlying HCV resistance to antiviral drugs. Current knowledge on these various issues is reviewed in the present article.

Antiviral Agents↗
PubMed2005

Complement profile in childhood immune thrombocytopenic purpura: a prospective pilot study.

Immune thrombocytopenic purpura (ITP) is a frequent, usually acute hematologic complication of viral diseases in children. Its evolution is usually benign with spontaneous resolution. Some authors have raised the hypothesis of a possible role of the complement system in the pathogenesis of ITP. In the present study, we measured the complement system components in 25 children with ITP. The complement system was abnormal in most patients with ITP as compared with the control group: 20 of the 25 patients had at least one low-component level. The most affected components were properdin, factor H (p=0.005 and p=0.001, respectively), C1q, C9, and factor B. Our results may indicate a possible role for the complement system in the pathogenesis of pediatric ITP.

Adolescent↗
PubMed1985

Comparative study of DHBV DNA levels and endogenous DNA polymerase activity in naturally infected ducklings in France.

Duck hepatitis B virus (DHBV) was found in the serum of 1-6% of Pekin ducklings originated from French commercial flocks. The viremia was followed in the serum of 5 ducklings over a span of 3 mth by monitoring the levels of DHBV DNA and the endogenous DNA polymerase (DNAp) activity. The DHBV DNA levels in serum were quantified either by the DNA dot hybridization technique including counting of retained radioactivity, or by successive dilutions of each serum sample followed by DNA hybridization. The counting of the retained radioactivity was plotted on a curve and its evolution compared with that of viral DNAp activity. DHBV DNA levels in serum, estimated by both methods paralleled those of the DNAp activity, which peaked at the 4th or 5th week posthatch to decrease and fluctuate thereafter. Occasional discordance between DHBV DNA levels and the endogenous DNAp activity was observed, which could be correlated with the degree of repair of the single stranded gap of serum DHBV DNA. Parallel follow up studies comparing quantitative estimations of serum viral DNA and of DNAp activity, as presented here, may provide some clues for the understanding of the mechanisms involved in the establishment of the HEPA DNA virus carrier state. Such comparative studies may also be crucial for optimal monitoring of antiviral drugs in both human clinical trials and animal experimental studies.

Animals↗
PubMed2004

From atoms to systems: a cross-disciplinary approach to complement-mediated functions.

With an ever-increasing wealth of information made available to researchers from expanding genomic sequence and protein structure databases, traditional experimentation and research are being drastically revisited. The unidirectional study of single molecules and pathways is being replaced by a combinatorial and cross-disciplinary platform that investigates interactive biological systems and dynamic networks. The complement system constitutes an ideal paradigm of how this concept is being applied in the field of contemporary immunology. Our laboratory has adopted such a cross-disciplinary approach in elucidating key aspects of complement functions and determining the role of several complement proteins in both inflammatory and developmental processes. Here we discuss recent findings pertaining to the rational development of complement inhibitors, our studies on protein-protein interactions and our progress in the study of viral immune evasion and complement evolution. Furthermore, we present recent studies implicating complement components in complex developmental processes, such as organ regeneration, hematopoietic development, and stem cell engraftment.

Animals↗
PubMed2004

Engineering a thermostable human prolyl endopeptidase for antibody-directed enzyme prodrug therapy.

We present a new antibody-directed enzyme prodrug therapy strategy (ADEPT) based on a post-proline cleaving endopeptidase and prodrugs, in which cytotoxic moieties are linked to a proline-containing peptide. Human prolyl endopeptidase was expressed in Escherichia coli and purified to homogeneity. The enzyme was active in buffer and in human serum but was rapidly thermally inactivated by incubation at 37 degrees C, thus preventing applications in vivo. While prolyl endopeptidase display on filamentous phage abolished viral infectivity and prevented directed evolution strategies based on phage display, we robotically screened 10752 individual colonies of mutant enzymes using a fluorogenic assay to improve enzyme stability. A single amino acid mutation (Glu289 --> Gly) improved protein stability, resulting in a half-life of 16 h at 37 degrees C in phosphate buffer. Two prodrugs were synthesized, in which an N-protected glycine-proline dipeptide was covalently coupled to doxorubicin and melphalan. (Benzyloxycarbonyl)glycylprolylmelphalan, but not the more sterically hindered doxorubicin prodrug, could be efficiently activated by prolyl endopeptidase [specific activity = 813.3 nmol min(-1) (mg of enzyme)(-1) at 25 degrees C]. The melphalan prodrug was essentially nontoxic to CHO, F9 teratocarcinoma, MCF7 breast adenocarcinoma, and p3U1 mouse myeloma cells up to millimolar concentrations, while prodrug incubation with the engineered prolyl endopeptidase mutant led to a cell killing profile superimposable to the one of melphalan. The prolyl endopeptidase mutant was then chemically coupled to the human antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis. The resulting immunoconjugate retains antigen binding and enzymatic activity, thus opening the way to anticancer ADEPT applications.

Animals↗
PubMed2005

The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host.

Mammalian influenza viruses are descendants of avian strains that crossed the species barrier and underwent further adaptation. Since 1997 in southeast Asia, H5N1 highly pathogenic avian influenza viruses have been causing severe, even fatal disease in humans. Although no lineages of this subtype have been established until now, such repeated events may initiate a new pandemic. As a model of species transmission, we used the highly pathogenic avian influenza virus SC35 (H7N7), which is low-pathogenic for mice, and its lethal mouse-adapted descendant SC35M. Specific mutations in SC35M polymerase considerably increase its activity in mammalian cells, correlating with high virulence in mice. Some of these mutations are prevalent in chicken and mammalian isolates, especially in the highly pathogenic H5N1 viruses from southeast Asia. These activity-enhancing mutations of the viral polymerase complex demonstrate convergent evolution in nature and, therefore, may be a prerequisite for adaptation to a new host paving the way for new pandemic viruses.

Adaptation, Physiological↗
PubMed2003

Death from the Nile crosses the Atlantic: the West Nile Fever story.

The present paper reviews the American epidemic of West Nile Fever (WNF), which is the largest recorded outbreak ever. The epidemiological consequences of introducing a novel and immunologically unknown pathogen in a previously unexposed population and the possible evolution of a more pathogenic viral strain are discussed. In view of recent reports of imported cases in Denmark the issue of possible disease spread to Scandinavia is likewise addressed. However, the main scope of the article is to provide the clinician with an overview of the natural history, epidemiology and clinical characteristics of the disease.

Communicable Disease Control↗
PubMed1998

Phlebotomus-transmitted toscana virus infections of the central nervous system: a seven-year experience in Tuscany.

Toscana virus (TOSv) is a recently discovered Phlebotomus-transmitted human pathogen involved in acute infections of the central nervous system (CNS) occurring during the summer in natural foci in Italy. The purpose of this prospective study was to investigate the role of this virus in 170 patients with meningitis-meningoencephalitis of suspected viral origin, admitted to the Departments of Infectious Diseases at the Siena Hospital from 1990 to 1996. Infections caused by tick-borne encephalitis virus (TBEv) and TOSv or other neurotropic viruses were routinely diagnosed by means of conventional virological methods. 89 cases were attributed to TOSv, about 10% of which were Europeans on vacation in Tuscany. All of the TOSv-positive cases were observed during the summer and were residents of hilly areas in Siena and its province at an altitude not above 500 m. An increase in the number of cases was observed over the years, with a higher incidence among younger people. The clinical picture was similar to that observed in other viral infections of the CNS. Evolution was benign in all cases; in 2 subjects symptoms and signs of encephalitis were present.

Acute Disease↗
PubMed1994

Phylogenetic classification of human T cell leukaemia/lymphoma virus type I genotypes in five major molecular and geographical subtypes.

Proviral DNA was obtained from ex vivo peripheral blood mononuclear cells of 75 human T cell leukaemia/lymphoma virus type I (HTLV-I)-infected individuals who were either asymptomatic or had adult T cell leukaemia or tropical spastic paraparesis/HTLV-I-associated myelopathy. Amplified long terminal repeats (LTRs) were analysed for restriction fragment length polymorphisms (RFLPs). The results, together with previously published LTR data (a total of 180 specimens analysed), showed the presence of 12 different RFLP profiles with four major molecular subtypes. Furthermore, a fragment of 413 bp (nucleotides 22 to 434) of the U3/R region was sequenced for 12 new HTLV-I specimens originating from Central and West Africa (8 cases), Iran (1 case), Caribbean (2 cases) and Reunion Island (1 case). Phylogenetic analysis using three different techniques (maximum parsimony, neighbour-joining and UPGMA) comparing these 12 strains (including four new African HTLV-I variants) with the 30 published partial HTLV-I LTR sequences (nt 120 to 434) showed the existence of clusters of molecular variants in discrete geographical areas. The topology of the phylogenetic trees is thought to reflect HTLV-I evolution and the migrations of virally infected populations in the recent or distant past. Furthermore, there was a nearly perfect concordance between the clustering based on the LTR sequence homologies and the LTR RFLP subtypes suggesting that this rapid and simple technique is well suited to the investigation of HTLV-I molecular epidemiology. These results allow a new phylogenetic classification of HTLV-I genotypes into five major molecular subtypes: Cosmopolitan (C) subtype widespread all over the world, Japanese (J) subtype, West African (WA) subtype. Central African (CA) subtype and Melanesian (M) subtype.

Africa↗
PubMed2025

Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies.

Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding in vivo viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope (env) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify in vivo routes and parallelism underlying HIV escape from each bNAb, providing new insights into this evolutionary process: 10-1074 escape is restricted to a small number of previously documented pathways, but these escape mutations 1) pre-exist in intra-host viral populations before therapy, 2) are not all equally preferred, and 3) emerge with a high degree of genetic parallelism within and across viral populations. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one population rarely emerge or spread in other populations, but often still exhibit parallel evolutionary responses within their host. That bNAbs elicit starkly different in vivo escape profiles depending on their Env target exposes the limitations of generalizing escape patterns across therapies and highlights the substantial challenges in predicting a viral population's bNAb susceptibility from genetic diversity alone.

Journal Article↗
PubMed2006

Physical theory of the competition that allows HIV to escape from the immune system.

Competition within the immune system may degrade immune control of viral infections. We formalize the evolution that occurs in both HIV-1 and the immune system quasispecies. Inclusion of competition in the immune system leads to a novel balance between the immune response and HIV-1, in which the eventual outcome is HIV-1 escape rather than control. The analytical model reproduces the three stages of HIV-1 infection. We propose a vaccine regimen that may be able to reduce competition between T cells, potentially eliminating the third stage of HIV-1.

Biological Evolution↗