The RNA synthesis machinery of negative-stranded RNA viruses

Ortı́n, Juan; Martín‐Benito, Jaime

doi:10.1016/j.virol.2015.03.018

Cited by 81 publications

(84 citation statements)

References 188 publications

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“…Our results do not distinguish between antibodies that interact with the different macromolecular complexes of GP, and studies that can associate host responses with each isoform may be important for development of vaccines and therapeutics. For further consideration, protein coding sequences differ slightly among isolates within a filovirus species and also within replicating populations of any isolate, as driven by factors such as the low fidelity of the RNA polymerase (47). The EBOV variant that precipitated the 2014 epidemic in Western Africa forms a distinct genetic lineage that diverges from previously studied isolates (48), including minor changes in amino acid sequences for GP.…”

Section: Discussionmentioning

confidence: 99%

Human Survivors of Disease Outbreaks Caused by Ebola or Marburg Virus Exhibit Cross-Reactive and Long-Lived Antibody Responses

Natarajan

Jensen

Keasey

et al. 2016

Clin Vaccine Immunol

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A detailed understanding of serological immune responses to Ebola and Marburg virus infections will facilitate the development of effective diagnostic methods, therapeutics, and vaccines. We examined antibodies from Ebola or Marburg survivors 1 to 14 years after recovery from disease, by using a microarray that displayed recombinant nucleoprotein (NP), viral protein 40 (VP40), envelope glycoprotein (GP), and inactivated whole virions from six species of filoviruses. All three outbreak cohorts exhibited significant antibody responses to antigens from the original infecting species and a pattern of additional filoviruses that varied by outbreak. NP was the most cross-reactive antigen, while GP was the most specific. Antibodies from survivors of infections by Marburg marburgvirus (MARV) species were least cross-reactive, while those from survivors of infections by Sudan virus (SUDV) species exhibited the highest cross-reactivity. Based on results revealed by the protein microarray, persistent levels of antibodies to GP, NP, and VP40 were maintained for up to 14 years after infection, and survival of infection caused by one species imparted cross-reactive antibody responses to other filoviruses.

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Section: Discussionmentioning

confidence: 99%

Human Survivors of Disease Outbreaks Caused by Ebola or Marburg Virus Exhibit Cross-Reactive and Long-Lived Antibody Responses

Natarajan

Jensen

Keasey

et al. 2016

Clin Vaccine Immunol

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“…The Filoviridae family includes Ebola virus (EBOV) and Marburg (MARV) virus, which use a negative sense RNA genome to replicate in the host cell (2). To date, no FDAapproved vaccines or therapeutics are available for EBOV or MARV and with fatality rates as high as 90% (3,4), these viruses are classified as category A pathogens by the NIH.…”

Section: Introductionmentioning

confidence: 99%

A cationic, C-terminal patch and structural rearrangements in Ebola virus matrix VP40 protein control its interactions with phosphatidylserine

Vecchio

Frick

Jeevan

et al. 2018

Journal of Biological Chemistry

134

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Ebola virus (EBOV) is a filamentous lipid-enveloped virus that causeshemorrhagic fever with a high fatality rate. Viral protein 40 (VP40) is the major EBOV matrix protein and regulates viral budding from the plasma membrane. VP40 is a transformer/morpheein that can structurally rearrange its native homodimer into either a hexameric filament that facilitates viral budding or a RNA-binding octameric ring that regulates viral transcription. VP40 associates with plasma-membrane lipids such as phosphatidylserine (PS), and this association is critical to budding from the host cell. However, it is poorly understood how different VP40 structures interact with PS, what essential residues are involved in this association, and whether VP40 has true selectivity for PS among different glycerophospholipid headgroups. In this study, we used lipid-binding assays, MD simulations, and cellular imaging to investigate the molecular basis of VP40-PS interactions and to determine whether different VP40 structures (i.e. monomer, dimer, and octamer) can interact with PScontaining membranes. Results from quantitative analysis indicated that VP40 associates with PS vesicles via a cationic patch in the C-terminal domain (Lys-224, 225 and Lys-274, 275). Substitutions of these residues with alanine reduced PSvesicle binding by >40-fold and abrogated VP40 localization to the plasma membrane. Dimeric VP40 had 2-fold greater affinity for PS-containing membranes than the monomer, whereas binding of the VP40 octameric ring was reduced by nearly 10-fold. Taken together, these results suggest http://www.jbc.org/cgi

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“…Interestingly, filovirus VP35 proteins are not highly phosphorylated like other phosphoprotein homologs (3,4). The genomes of NNSVs are never found as naked RNAs in virions or infected cells (5)(6)(7). Instead, they are completely encapsidated by the viral nucleoprotein (5-7), termed NP in the case of filoviruses and N in other NNSVs.…”

mentioning

confidence: 99%

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

Bruhn

Kirchdoerfer

Urata

et al. 2017

J Virol

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Marburg virus (MARV) is a highly pathogenic filovirus that is classified in a genus distinct from that of Ebola virus (EBOV) (genera Marburgvirus and Ebolavirus, respectively). Both viruses produce a multifunctional protein termed VP35, which acts as a polymerase cofactor, a viral protein chaperone, and an antagonist of the innate immune response. VP35 contains a central oligomerization domain with a predicted coiled-coil motif. This domain has been shown to be essential for RNA polymerase function. Here we present crystal structures of the MARV VP35 oligomerization domain. These structures and accompanying biophysical characterization suggest that MARV VP35 is a trimer. In contrast, EBOV VP35 is likely a tetramer in solution. Differences in the oligomeric state of this protein may explain mechanistic differences in replication and immune evasion observed for MARV and EBOV.IMPORTANCE Marburg virus can cause severe disease, with up to 90% human lethality. Its genome is concise, only producing seven proteins. One of the proteins, VP35, is essential for replication of the viral genome and for evasion of host immune responses. VP35 oligomerizes (self-assembles) in order to function, yet the structure by which it assembles has not been visualized. Here we present two crystal structures of this oligomerization domain. In both structures, three copies of VP35 twist about each other to form a coiled coil. This trimeric assembly is in contrast to tetrameric predictions for VP35 of Ebola virus and to known structures of homologous proteins in the measles, mumps, and Nipah viruses. Distinct oligomeric states of the Marburg and Ebola virus VP35 proteins may explain differences between them in polymerase function and immune evasion. These findings may provide a more accurate understanding of the mechanisms governing VP35's functions and inform the design of therapeutics. KEYWORDS VP35, filovirus, RNA-dependent RNA polymerase, phosphoprotein, coiled coil, oligomerization, Marburg virus, Ebola virus, X-ray crystallography M arburg virus (MARV) can cause severe hemorrhagic fever in humans with high case fatality rates. Though less well known than its relative Ebola virus (EBOV), MARV was the first filovirus identified. MARV has caused sporadic outbreaks since its identification in 1968, including the 1998 to 2000 outbreak in the Democratic Republic of the Congo, which occurred with 83% lethality, and the 2004 to 2005 outbreak in Angola, which occurred with 90% lethality (1). Currently, there are no approved vaccines or therapeutics available to treat individuals infected with MARV. Despite sharing ϳ50% nucleotide sequence identity, MARV and EBOV have several striking functional differences. MARV does not produce sGP or ssGP protein and does not require VP30 for transcription. MARV and EBOV also exhibit differences in their immune evasion strategies (2).

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The RNA synthesis machinery of negative-stranded RNA viruses

Cited by 81 publications

References 188 publications

Human Survivors of Disease Outbreaks Caused by Ebola or Marburg Virus Exhibit Cross-Reactive and Long-Lived Antibody Responses

Human Survivors of Disease Outbreaks Caused by Ebola or Marburg Virus Exhibit Cross-Reactive and Long-Lived Antibody Responses

A cationic, C-terminal patch and structural rearrangements in Ebola virus matrix VP40 protein control its interactions with phosphatidylserine

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

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