Advertisement

Topics

T-705 induces lethal mutagenesis in Ebola and Marburg populations in macaques.

08:00 EDT 10th June 2019 | BioPortfolio

Summary of "T-705 induces lethal mutagenesis in Ebola and Marburg populations in macaques."

Nucleoside analogues (NA) disrupt RNA viral RNA-dependent RNA polymerase (RdRP) function and fidelity for multiple viral families. The mechanism of action (MOA) of T-705 has been attributed alternatively or concurrently to chain termination and lethal mutagenesis depending on the viral species during in vitro studies. In this study, we evaluated the effect of T-705 on the viral population in non-human primates (NHPs) after challenge with Ebola virus (EBOV) or Marburg virus (MARV) to identify the predominant in vivo MOA. We used common virological assays in conjunction with deep sequencing to characterize T-705 effects. T-705 exhibited antiviral activity that was associated with a reduction in specific infectivity and an accumulation of low frequency nucleotide variants in plasma samples collected day 7 post infection. Stranded analysis of deep sequencing data to identify chain termination demonstrated no change in the transcriptional gradient in negative stranded viral reads and minimal changes in positive stranded viral reads in T-705 treated animals, questioning as a MOA in vivo. These findings indicate that lethal mutagenesis is a MOA of T-705 that may serve as an indication of therapeutic activity of NAs for evaluation in clinical settings. This study expands our understanding of MOAs of these compounds for the Filovirus family and provides further evidence that lethal mutagenesis could be a preponderant MOA for this class of therapeutic compounds.

Affiliation

Journal Details

This article was published in the following journal.

Name: Antiviral research
ISSN: 1872-9096
Pages:

Links

DeepDyve research library

PubMed Articles [7080 Associated PubMed Articles listed on BioPortfolio]

Complete protection of the BALB/c and C57BL/6J mice against Ebola and Marburg virus lethal challenges by pan-filovirus T-cell epigraph vaccine.

There are a number of vaccine candidates under development against a small number of the most common outbreak filoviruses all employing the virus glycoprotein (GP) as the vaccine immunogen. However, a...

Antibody-mediated virus neutralization is not a universal mechanism of Marburg, Ebola or Sosuga virus clearance in Egyptian rousette bats.

Although bats are increasingly being recognized as natural reservoir hosts of emerging zoonotic viruses, little is known about how they control and clear virus infection in the absence of clinical dis...

In Vitro Characterization and In Vivo Effectiveness of Ebola Virus Specific Equine Polyclonal F(ab')2.

There is no vaccine or approved therapy against lethal Ebola virus (EBOV). We investigated a proven technology platform to produce polyclonal IgG fragments, F(ab')2, against EBOV. Horses immunized wit...

Population persistence under high mutation rate: from evolutionary rescue to lethal mutagenesis.

Populations may genetically adapt to severe stress that would otherwise cause their extirpation. Recent theoretical work, combining stochastic demography with Fisher's geometric model of adaptation, h...

Current status of small molecule drug development for Ebola virus and other filoviruses.

The filovirus family includes some of the deadliest viruses known, including Ebola virus and Marburg virus. These viruses cause periodic outbreaks of severe disease that can be spread from person to p...

Clinical Trials [1675 Associated Clinical Trials listed on BioPortfolio]

Evaluating an Ebola and a Margurg Vaccine in Uganda

This study will test two new vaccines, one for Ebola and one for Marburg virus, to see if they are safe, if they have side effects, and if they create an immune response in people who rece...

Ebola and Marburg Virus Vaccines

This study will determine if experimental vaccines to prevent Ebola virus infection and Marburg virus infection are safe and what side effects, if any, they cause. Ebola virus infection ma...

cAd3-Marburg Vaccine in Healthy Adults

RV 507 is a Phase I, open-label study to examine safety, tolerability and immunogenicity of an investigational Marburg vaccine given by intramuscular (IM) injection to healthy adults. The ...

Trial to Evaluate Safety and Immunogenicity of an Ebola Zaire Vaccine in Healthy Adults

The purpose of this study is to assess the safety profile of the Zaire Ebola vaccine and the strength of the immune response.

Experimental Ebola Vaccine Trial

This study will test the safety of an experimental vaccine developed to protect against Ebola virus infection and to determine if the vaccine induces an immune response to the virus. The E...

Medical and Biotech [MESH] Definitions

A highly fatal, acute hemorrhagic fever, clinically very similar to MARBURG VIRUS DISEASE, caused by EBOLAVIRUS, first occurring in the Sudan and adjacent northwestern (what was then) Zaire.

An Ig domain-containing membrane receptor for HEPATITIS A VIRUS; EBOLA VIRUS; MARBURG VIRUS; and DENGUE VIRUS. It may also function to modulate ASTHMA and HYPERSENSITIVITY.

Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.

Vaccines or candidate vaccines used to prevent EBOLA HEMORRHAGIC FEVER.

Mutagenesis where the mutation is caused by the introduction of foreign DNA sequences into a gene or extragenic sequence. This may occur spontaneously in vivo or be experimentally induced in vivo or in vitro. Proviral DNA insertions into or adjacent to a cellular proto-oncogene can interrupt GENETIC TRANSLATION of the coding sequences or interfere with recognition of regulatory elements and cause unregulated expression of the proto-oncogene resulting in tumor formation.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topics

Marburg and Ebola Virus Infections
Ebola virus and Marburg virus are related viruses that cause hemorrhagic fevers — illnesses marked by severe bleeding (hemorrhage), organ failure and, in many cases, death. Both viruses are native to Africa, where sporadic outbreaks have occurred f...

Polymerase Chain Reaction (PCR)
PCR (Polymerase Chain Reaction) uses the ability of DNA polymerase (enzymes that create DNA molecules by assembling nucleotides, the building blocks of DNA. These enzymes are essential to DNA replication and usually work in pairs to create two ident...

Tropical Medicine
Tropical Medicine is the study of diseases more commonly found in tropical regions than elsewhere. Examples of these diseases are malaria, yellow fever, Chagas disease, Dengue, Helminths, African trypanosomiasis, Leishmaniasis, Leprosy, Lymphatic filaria...


Searches Linking to this Article