scholarly journals Modelling Mutation in Equine Infectious Anemia Virus Infection Suggests a Path to Viral Clearance with Repeated Vaccination

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2450
Author(s):  
Elissa J. Schwartz ◽  
Christian Costris-Vas ◽  
Stacey R. Smith

Equine Infectious Anemia Virus (EIAV) is a lentivirus similar to HIV that infects horses. Clinical and experimental studies demonstrating immune control of EIAV infection hold promise for efforts to produce an HIV vaccine. Antibody infusions have been shown to block both wild-type and mutant virus infection, but the mutant sometimes escapes. Using these data, we develop a mathematical model that describes the interactions between antibodies and both wild-type and mutant virus populations, in the context of continual virus mutation. The aim of this work is to determine whether repeated vaccinations through antibody infusions can reduce both the wild-type and mutant strains of the virus below one viral particle, and if so, to examine the vaccination period and number of infusions that ensure eradication. The antibody infusions are modelled using impulsive differential equations, a technique that offers insight into repeated vaccination by approximating the time-to-peak by an instantaneous change. We use impulsive theory to determine the maximal vaccination intervals that would be required to reduce the wild-type and mutant virus levels below one particle per horse. We show that seven boosts of the antibody vaccine are sufficient to eradicate both the wild-type and the mutant strains. In the case of a mutant virus infection that is given infusions of antibodies targeting wild-type virus (i.e., simulation of a heterologous infection), seven infusions were likewise sufficient to eradicate infection, based upon the data set. However, if the period between infusions was sufficiently increased, both the wild-type and mutant virus would eventually persist in the form of a periodic orbit. These results suggest a route forward to design antibody-based vaccine strategies to control viruses subject to mutant escape.

2015 ◽  
Vol 89 (13) ◽  
pp. 6945-6951 ◽  
Author(s):  
Elissa J. Schwartz ◽  
Seema Nanda ◽  
Robert H. Mealey

Lentivirus escape from neutralizing antibodies (NAbs) is not well understood. In this work, we quantified antibody escape of a lentivirus, using antibody escape data from horses infected with equine infectious anemia virus. We calculated antibody blocking rates of wild-type virus, fitness costs of mutant virus, and growth rates of both viruses. These quantitative kinetic estimates of antibody escape are important for understanding lentiviral control by antibody neutralization and in developing NAb-eliciting vaccine strategies.


2007 ◽  
Vol 82 (4) ◽  
pp. 1628-1637 ◽  
Author(s):  
Melinda A. Brindley ◽  
Wendy Maury

ABSTRACT Entry of wild-type lentivirus equine infectious anemia virus (EIAV) into cells requires a low-pH step. This low-pH constraint implicates endocytosis in EIAV entry. To identify the endocytic pathway involved in EIAV entry, we examined the entry requirements for EIAV into two different cells: equine dermal (ED) cells and primary equine endothelial cells. We investigated the entry mechanism of several strains of EIAV and found that both macrophage-tropic and tissue culture-adapted strains utilize clathrin-coated pits for entry. In contrast, a superinfecting strain of EIAV, EIAVvMA-1c, utilizes two mechanisms of entry. In cells such as ED cells that EIAVvMA-1c is able to superinfect, viral entry is pH independent and appears to be mediated by plasma membrane fusion, whereas in cells where no detectable superinfection occurs, EIAVvMA-1c entry that is low-pH dependent occurs through clathrin-coated pits in a manner similar to wild-type virus. Regardless of the mechanism of entry being utilized, the internalization kinetics of EIAV is rapid with 50% of cell-associated virions internalizing within 60 to 90 min. Cathepsin inhibitors did not prevent EIAV entry, suggesting that the low-pH step required by wild-type EIAV is not required to activate cellular cathepsins.


2008 ◽  
Vol 82 (19) ◽  
pp. 9425-9432 ◽  
Author(s):  
Melinda A. Brindley ◽  
Baoshan Zhang ◽  
Ronald C. Montelaro ◽  
Wendy Maury

ABSTRACT Wild-type strains of equine infectious anemia virus (EIAV) prevent superinfection of previously infected cells. A variant strain of virus that spontaneously arose during passage, EIAVvMA-1c, can circumvent this mechanism in some cells, such as equine dermis (ED) cells, but not in others, such as equine endothelial cells. EIAVvMA-1c superinfection of ED cells results in a buildup of unintegrated viral DNA and rapid killing of the cell monolayer. Here, we examined the mechanism of resistance that is used by EIAV to prevent superinfection and explored the means by which EIAVvMA-1c overcomes this restriction. We found that the cellular receptor used by EIAV, equine lentivirus receptor 1 (ELR1), remains on the surface of cells chronically infected with EIAV, suggesting that wild-type EIAV interferes with superinfection by masking ELR1. The addition of soluble wild-type SU protein to the medium during infection blocked infection by wild-type strains of virus, implicating SU as the viral protein responsible for interfering with virion entry into previously infected cells. Additionally, interference of wild-type EIAV binding to ELR1 by the addition of either anti-ELR1 antibodies or the ELR1 ectodomain prevented entry of the wild-type strains of EIAV into two permissive cell populations. Many of these same interference treatments prevented EIAVvMA-1c infection of endothelial cells but only modestly affected the ability of EIAVvMA-1c to enter and kill previously infected ED cells. These findings indicate that EIAVvMA-1c retains the ability to use ELR1 for entry and suggest that this virus can interact with an additional, unidentified receptor to superinfect ED cells.


2019 ◽  
Author(s):  
Xufang Deng ◽  
Yafang Chen ◽  
Anna M. Mielech ◽  
Matthew Hackbart ◽  
Kristina R. Kesely ◽  
...  

AbstractCoronaviruses express a multifunctional papain-like protease, termed PLP2. PLP2 acts as a protease that cleaves the viral replicase polyprotein, and a deubiquitinating (DUB) enzyme which removes ubiquitin moieties from ubiquitin-conjugated proteins. Previous in vitro studies implicated PLP2 DUB activity as a negative regulator of the host interferon (IFN) response, but the role of DUB activity during virus infection was unknown. Here, we used X-ray structure-guided mutagenesis and functional studies to identify amino acid substitutions within the ubiquitin-binding surface of PLP2 that reduced DUB activity without affecting polyprotein processing activity. We engineered a DUB mutation (Asp1772 to Ala) into a murine coronavirus and evaluated the replication and pathogenesis of the DUB mutant virus (DUBmut) in cultured macrophages and in mice. We found that the DUBmut virus replicates similarly as the wild-type virus in cultured cells, but the DUBmut virus activates an IFN response at earlier times compared to the wild-type virus infection in macrophages, consistent with DUB activity negatively regulating the IFN response. We compared the pathogenesis of the DUBmut virus to the wild-type virus and found that the DUBmut-infected mice had a statistically significant reduction (p<0.05) in viral titer in livers and spleens at day 5 post-infection, albeit both wild-type and DUBmut virus infections resulted in similar liver pathology. Overall, this study demonstrates that structure-guided mutagenesis aids the identification of critical determinants of PLP2-ubiquitin complex, and that PLP2 DUB activity plays a role as an interferon antagonist in coronavirus pathogenesis.ImportanceCoronaviruses employ a genetic economy by encoding multifunctional proteins that function in viral replication and also modify the host environment to disarm the innate immune response. The coronavirus papain-like protease 2 (PLP2) domain possesses protease activity, which cleaves the viral replicase polyprotein, and also DUB activity (de-conjugating ubiquitin/ubiquitin-like molecules from modified substrates) using identical catalytic residues. To separate the DUB activity from the protease activity, we employed a structure-guided mutagenesis approach and identified residues that are important for ubiquitin-binding. We found that mutating the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease activity. We engineered a recombinant murine coronavirus to express the DUB mutant and showed that the DUB mutant virus activated an earlier type I interferon response in macrophages and exhibited reduced pathogenesis in mice. The results of this study demonstrate that PLP2/DUB is an interferon antagonist and a virulence trait of coronaviruses.


2015 ◽  
Vol 47 (1) ◽  
pp. 25-28 ◽  
Author(s):  
Irene Alvarez ◽  
Fabiana Cipolini ◽  
Andrés Wigdorovitz ◽  
Karina Trono ◽  
Maria E. Barrandeguy

2013 ◽  
Vol 44 (1) ◽  
pp. 113 ◽  
Author(s):  
Pompei Bolfa ◽  
Marie Nolf ◽  
Jean-Luc Cadoré ◽  
Cornel Catoi ◽  
Fabienne Archer ◽  
...  

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