The Experts below are selected from a list of 3486 Experts worldwide ranked by ideXlab platform
Jeffrey I Cohen - One of the best experts on this subject based on the ideXlab platform.
-
update on new antivirals under development for the treatment of double stranded dna virus infections
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Lesia K Dropulic, Jeffrey I CohenAbstract:All of the currently available antiviral agents used to treat double-stranded (ds) DNA Viruses inhibit the same target, the viral DNA polymerase, with the exception of interferon-α. With increasing reports of the development of resistance of herpes simplex virus, cytomegalovirus, and hepatitis B virus to some of these drugs, new antiviral agents are needed for these infections. Additionally, no drugs are approved to treat several DNA virus infections including those caused by adenovirus, smallpox, molluscum contagiosum, and BK virus. We report on the status of 10 new antiviral drugs for the treatment of dsDNA Viruses. CMX-001 has broad activity against dsDNA Viruses; 3 helicase-primase inhibitors, marabavir, and FV-100 have activity against certain herpesViruses; ST-246 inhibits poxViruses; GS-9191 inhibits papillomaViruses; and clevudine and emtricitabine are active against hepatitis B virus. Most of these drugs have completed at least phase I trials in humans and several are in additional clinical trials.
-
Update on New Antivirals Under Development for the Treatment of Double‐Stranded DNA Virus Infections
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Lesia K Dropulic, Jeffrey I CohenAbstract:All of the currently available antiviral agents used to treat double-stranded (ds) DNA Viruses inhibit the same target, the viral DNA polymerase, with the exception of interferon-α. With increasing reports of the development of resistance of herpes simplex virus, cytomegalovirus, and hepatitis B virus to some of these drugs, new antiviral agents are needed for these infections. Additionally, no drugs are approved to treat several DNA virus infections including those caused by adenovirus, smallpox, molluscum contagiosum, and BK virus. We report on the status of 10 new antiviral drugs for the treatment of dsDNA Viruses. CMX-001 has broad activity against dsDNA Viruses; 3 helicase-primase inhibitors, marabavir, and FV-100 have activity against certain herpesViruses; ST-246 inhibits poxViruses; GS-9191 inhibits papillomaViruses; and clevudine and emtricitabine are active against hepatitis B virus. Most of these drugs have completed at least phase I trials in humans and several are in additional clinical trials.
Joshua A Hill - One of the best experts on this subject based on the ideXlab platform.
-
in vitro comparison of currently available and investigational antiviral agents against pathogenic human double stranded dna Viruses a systematic literature review
Antiviral Research, 2019Co-Authors: Joshua A Hill, Sebastian Voigt, Karl S PeggsAbstract:Abstract Background Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA Viruses. Methods A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA Viruses; 3) in vitro activity. We summarized data from 210 publications. Results Activity against ≤3 Viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 Viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC 50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all Viruses except papillomaViruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC 50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus. Conclusion Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC 50 values. These findings could assist clinical practice and developmental research.
-
in vitro comparison of currently available and investigational antiviral agents against pathogenic human double stranded dna Viruses a systematic literature review
Antiviral Research, 2019Co-Authors: Joshua A Hill, Sebastian Voigt, Karl S PeggsAbstract:Abstract Background Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA Viruses. Methods A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA Viruses; 3) in vitro activity. We summarized data from 210 publications. Results Activity against ≤3 Viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 Viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC 50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all Viruses except papillomaViruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC 50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus. Conclusion Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC 50 values. These findings could assist clinical practice and developmental research.
-
the cumulative burden of double stranded dna virus detection after allogeneic hct is associated with increased mortality
Blood, 2017Co-Authors: Joshua A Hill, Bryan T Mayer, Wendy Leisenring, Meeili Huang, Terry Stevensayers, Filippo Milano, Colleen Delaney, Mohamed L Sorror, Brenda M SandmaierAbstract:: Strategies to prevent active infection with certain double-stranded DNA (dsDNA) Viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple Viruses and association of Viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple Viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 Viruses. Risk factors for detection of multiple Viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease (P values < .01). Absolute lymphocyte count of <200 cells/mm3 was associated with greater virus exposure on the basis of the maximum cumulative viral load area under the curve (AUC) (P = .054). The maximum cumulative viral load AUC was the best predictor of early (days 0-100) and late (days 101-365) overall mortality (adjusted hazard ratio [aHR] = 1.36, 95% confidence interval [CI] [1.25, 1.49], and aHR = 1.04, 95% CI [1.0, 1.08], respectively) after accounting for immune reconstitution and graft-versus-host disease. In conclusion, detection of multiple dsDNA Viruses was frequent after allogeneic HCT and had a dose-dependent association with increased mortality. These data suggest opportunities to improve outcomes with better antiviral strategies.
-
the cumulative burden of double stranded dna virus detection after allogeneic hct is associated with increased mortality
Blood, 2017Co-Authors: Joshua A Hill, Bryan T Mayer, Wendy Leisenring, Meeili Huang, Terry Stevensayers, Filippo Milano, Colleen Delaney, Mohamed L Sorror, Brenda M SandmaierAbstract:Strategies to prevent active infection with certain double-stranded DNA (dsDNA) Viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple Viruses and association of Viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple Viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 Viruses. Risk factors for detection of multiple Viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease ( P values 3 was associated with greater virus exposure on the basis of the maximum cumulative viral load area under the curve (AUC) ( P = .054). The maximum cumulative viral load AUC was the best predictor of early (days 0-100) and late (days 101-365) overall mortality (adjusted hazard ratio [aHR] = 1.36, 95% confidence interval [CI] [1.25, 1.49], and aHR = 1.04, 95% CI [1.0, 1.08], respectively) after accounting for immune reconstitution and graft-versus-host disease. In conclusion, detection of multiple dsDNA Viruses was frequent after allogeneic HCT and had a dose-dependent association with increased mortality. These data suggest opportunities to improve outcomes with better antiviral strategies.
Mart Krupovic - One of the best experts on this subject based on the ideXlab platform.
-
Global Organization and Proposed Megataxonomy of the Virus World
Microbiology and Molecular Biology Reviews, 2020Co-Authors: Eugene Koonin, Valerian V. Dolja, Mart Krupovic, Natalya Yutin, Arvind Varsani, Yuri Wolf, F. Murilo Zerbini, Jens KuhnAbstract:SUMMARY : Viruses and mobile genetic elements are molecular parasites or symbionts that coevolve with nearly all forms of cellular life. The route of virus replication and protein expression is determined by the viral genome type. Comparison of these routes led to the classification of Viruses into seven "Baltimore classes" (BCs) that define the major features of virus reproduction. However, recent phylogenomic studies identified multiple evolutionary connections among Viruses within each of the BCs as well as between different classes. Due to the modular organization of virus genomes, these relationships defy simple representation as lines of descent but rather form complex networks. Phylogenetic analyses of virus hallmark genes combined with analyses of gene-sharing networks show that replication modules of five BCs (three classes of RNA Viruses and two classes of reverse-transcribing Viruses) evolved from a common ancestor that encoded an RNA-directed RNA polymerase or a reverse transcriptase. Bona fide Viruses evolved from this ancestor on multiple, independent occasions via the recruitment of distinct cellular proteins as capsid subunits and other structural components of virions. The single-stranded DNA (ssDNA) Viruses are a polyphyletic class, with different groups evolving by recombination between rolling-circle-replicating plasmids, which contributed the replication protein, and positive-sense RNA Viruses, which contributed the capsid protein. The double-stranded DNA (dsDNA) Viruses are distributed among several large monophyletic groups and arose via the combination of distinct structural modules with equally diverse replication modules. Phylogenomic analyses reveal the finer structure of evolutionary connections among RNA Viruses and reverse-transcribing Viruses, ssDNA Viruses, and large subsets of dsDNA Viruses. Taken together, these analyses allow us to outline the global organization of the virus world. Here, we describe the key aspects of this organization and propose a comprehensive hierarchical taxonomy of Viruses.
-
Diversification of giant and large eukaryotic dsDNA Viruses predated the origin of modern eukaryotes
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Julien Guglielmini, Mart Krupovic, Anthony C. Woo, Patrick Forterre, Morgan GaiaAbstract:Giant and large eukaryotic double-stranded DNA Viruses from the Nucleo-Cytoplasmic Large DNA Virus (NCLDV) assemblage represent a remarkably diverse and potentially ancient component of the eukaryotic virome. However, their origin(s), evolution, and potential roles in the emergence of modern eukaryotes remain subjects of intense debate. Here we present robust phylogenetic trees of NCLDVs, based on the 8 most conserved proteins responsible for virion morphogenesis and informational processes. Our results uncover the evolutionary relationships between different NCLDV families and support the existence of 2 superclades of NCLDVs, each encompassing several families. We present evidence strongly suggesting that the NCLDV core genes, which are involved in both informational processes and virion formation, were acquired vertically from a common ancestor. Among them, the largest subunits of the DNA-dependent RNA polymerase were transferred between 2 clades of NCLDVs and proto-eukaryotes, giving rise to 2 of the 3 eukaryotic DNA-dependent RNA polymerases. Our results strongly suggest that these transfers and the diversification of NCLDVs predated the emergence of modern eukaryotes, emphasizing the major role of Viruses in the evolution of cellular domains.
-
Diversification of giant and large eukaryotic dsDNA Viruses predated the origin of modern eukaryotes
2018Co-Authors: Julien Guglielmini, Mart Krupovic, Anthony C. Woo, Patrick Forterre, Morgan GaiaAbstract:Abstract Giant and large eukaryotic double-stranded DNA Viruses from the Nucleo-Cytoplasmic Large DNA Virus (NCLDV) assemblage represent a remarkably diverse and potentially ancient component of the eukaryotic virome. However, their origin(s), evolution and potential roles in the emergence of modern eukaryotes remain a subject of intense debate. Since the characterization of the mimivirus in 2003, many big and giant Viruses have been discovered at a steady pace, offering a vast material for evolutionary investigations. In parallel, phylogenetic tools are constantly being improved, offering more rigorous approaches for reconstruction of deep evolutionary history of Viruses and their hosts. Here we present robust phylogenetic trees of NCLDVs, based on the 8 most conserved proteins responsible for virion morphogenesis and informational processes. Our results uncover the evolutionary relationships between different NCLDV families and support the existence of two superclades of NCLDVs, each encompassing several families. We present evidence strongly suggesting that the NCLDV core genes, which are involved in both informational processes and virion formation, were acquired vertically from a common ancestor. Among them, the largest subunits of the DNA-dependent RNA polymerase were seemingly transferred from two clades of NCLDVs to proto-eukaryotes, giving rise to two of the three eukaryotic DNA-dependent RNA polymerases. Our results strongly suggest that these transfers and the diversification of NCLDVs predated the emergence of modern eukaryotes, emphasizing the major role of Viruses in the evolution of cellular domains.
-
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue:DNA Habitats and Their RNA Inhabitants Evolution of double-stranded DNA Viruses of eukaryotes: from bacteriophages to transposons to giant Viruses
2016Co-Authors: Eugene V. Koonin, Mart Krupovic, Natalya YutinAbstract:Diverse eukaryotes including animals and protists are hosts to a broad variety of Viruses with double-stranded (ds) DNA genomes, from the largest known Viruses, such as pandoraViruses and mimiViruses, to tiny polyomaViruses. Recent comparative genomic analyses have revealed many evolutionary connections between dsDNA Viruses of eukaryotes, bacteriophages, transposable elements, and linear DNA plasmids. These findings provide an evolu-tionary scenario that derives several major groups of eukaryotic dsDNA Viruses, including the proposed order “Megavirales, ” adenoViruses, and virophages from a group of large virus-like transposons known as Polintons (Mav-ericks). The Polintons have been recently shown to encode two capsid proteins, suggesting that these elements lead a dual lifestyle with both a transposon and a viral phase and should perhaps more appropriately be named polin-toViruses. Here, we describe the recently identified evolutionary relationships between bacteriophages of the family Tectiviridae, polintoViruses, adenoViruses, virophages, large and giant DNA Viruses of eukaryotes of the proposed order “Megavirales, ” and linearmitochondrial and cytoplasmic plasmids.We outline an evolutionary scenario under which the polintoViruses were the first group of eukaryotic dsDNA Viruses that evolved from bacteriophages and became the ancestors of most large DNA Viruses of eukaryotes and a variety of other selfish elements. Distinct lines of origin are detectable only for herpesViruses (from a different bacteriophage root) and polyoma/papillomaViruses (from single-stranded DNA Viruses and ultimately from plasmids). Phylogenomic analysis of giant Viruses provide
-
The Double-Stranded DNA Virosphere as a Modular Hierarchical Network of Gene Sharing
mBio, 2016Co-Authors: Jaime Iranzo, Mart Krupovic, Eugene V. KooninAbstract:Virus genomes are prone to extensive gene loss, gain, and exchange and share no universal genes. Therefore, in a broad-scale study of virus evolution, gene and genome network analyses can complement traditional phylogenetics. We performed an exhaustive comparative analysis of the genomes of double-stranded DNA (dsDNA) Viruses by using the bipartite network approach and found a robust hierarchical modularity in the dsDNA virosphere. Bipartite networks consist of two classes of nodes, with nodes in one class, in this case genomes, being connected via nodes of the second class, in this case genes. Such a network can be partitioned into modules that combine nodes from both classes. The bipartite network of dsDNA Viruses includes 19 modules that form 5 major and 3 minor supermodules. Of these modules, 11 include tailed bacteriophages, reflecting the diversity of this largest group of Viruses. The module analysis quantitatively validates and refines previously proposed nontrivial evolutionary relationships. An expansive supermodule combines the large and giant Viruses of the putative order "Megavirales" with diverse moderate-sized Viruses and related mobile elements. All Viruses in this supermodule share a distinct morphogenetic tool kit with a double jelly roll major capsid protein. HerpesViruses and tailed bacteriophages comprise another supermodule, held together by a distinct set of morphogenetic proteins centered on the HK97-like major capsid protein. Together, these two supermodules cover the great majority of currently known dsDNA Viruses. We formally identify a set of 14 viral hallmark genes that comprise the hubs of the network and account for most of the intermodule connections. IMPORTANCE: Viruses and related mobile genetic elements are the dominant biological entities on earth, but their evolution is not sufficiently understood and their classification is not adequately developed. The key reason is the characteristic high rate of virus evolution that involves not only sequence change but also extensive gene loss, gain, and exchange. Therefore, in the study of virus evolution on a large scale, traditional phylogenetic approaches have limited applicability and have to be complemented by gene and genome network analyses. We applied state-of-the art methods of such analysis to reveal robust hierarchical modularity in the genomes of double-stranded DNA Viruses. Some of the identified modules combine highly diverse Viruses infecting bacteria, archaea, and eukaryotes, in support of previous hypotheses on direct evolutionary relationships between Viruses from the three domains of cellular life. We formally identify a set of 14 viral hallmark genes that hold together the genomic network.
Lesia K Dropulic - One of the best experts on this subject based on the ideXlab platform.
-
update on new antivirals under development for the treatment of double stranded dna virus infections
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Lesia K Dropulic, Jeffrey I CohenAbstract:All of the currently available antiviral agents used to treat double-stranded (ds) DNA Viruses inhibit the same target, the viral DNA polymerase, with the exception of interferon-α. With increasing reports of the development of resistance of herpes simplex virus, cytomegalovirus, and hepatitis B virus to some of these drugs, new antiviral agents are needed for these infections. Additionally, no drugs are approved to treat several DNA virus infections including those caused by adenovirus, smallpox, molluscum contagiosum, and BK virus. We report on the status of 10 new antiviral drugs for the treatment of dsDNA Viruses. CMX-001 has broad activity against dsDNA Viruses; 3 helicase-primase inhibitors, marabavir, and FV-100 have activity against certain herpesViruses; ST-246 inhibits poxViruses; GS-9191 inhibits papillomaViruses; and clevudine and emtricitabine are active against hepatitis B virus. Most of these drugs have completed at least phase I trials in humans and several are in additional clinical trials.
-
Update on New Antivirals Under Development for the Treatment of Double‐Stranded DNA Virus Infections
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Lesia K Dropulic, Jeffrey I CohenAbstract:All of the currently available antiviral agents used to treat double-stranded (ds) DNA Viruses inhibit the same target, the viral DNA polymerase, with the exception of interferon-α. With increasing reports of the development of resistance of herpes simplex virus, cytomegalovirus, and hepatitis B virus to some of these drugs, new antiviral agents are needed for these infections. Additionally, no drugs are approved to treat several DNA virus infections including those caused by adenovirus, smallpox, molluscum contagiosum, and BK virus. We report on the status of 10 new antiviral drugs for the treatment of dsDNA Viruses. CMX-001 has broad activity against dsDNA Viruses; 3 helicase-primase inhibitors, marabavir, and FV-100 have activity against certain herpesViruses; ST-246 inhibits poxViruses; GS-9191 inhibits papillomaViruses; and clevudine and emtricitabine are active against hepatitis B virus. Most of these drugs have completed at least phase I trials in humans and several are in additional clinical trials.
Karl S Peggs - One of the best experts on this subject based on the ideXlab platform.
-
in vitro comparison of currently available and investigational antiviral agents against pathogenic human double stranded dna Viruses a systematic literature review
Antiviral Research, 2019Co-Authors: Joshua A Hill, Sebastian Voigt, Karl S PeggsAbstract:Abstract Background Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA Viruses. Methods A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA Viruses; 3) in vitro activity. We summarized data from 210 publications. Results Activity against ≤3 Viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 Viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC 50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all Viruses except papillomaViruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC 50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus. Conclusion Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC 50 values. These findings could assist clinical practice and developmental research.
-
in vitro comparison of currently available and investigational antiviral agents against pathogenic human double stranded dna Viruses a systematic literature review
Antiviral Research, 2019Co-Authors: Joshua A Hill, Sebastian Voigt, Karl S PeggsAbstract:Abstract Background Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA Viruses. Methods A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA Viruses; 3) in vitro activity. We summarized data from 210 publications. Results Activity against ≤3 Viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 Viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC 50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all Viruses except papillomaViruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC 50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus. Conclusion Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC 50 values. These findings could assist clinical practice and developmental research.
