Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry

ABSTRACT Hendra virus and Nipah virus, two zoonotic paramyxoviruses in the genus Henipavirus, have recently emerged and continue to cause sporadic disease outbreaks in humans and animals. Mortality rates of up to 75% have been reported in humans, but there are presently no clinically licensed therapeutics for treating henipavirus-induced disease. A recent report indicated that chloroquine, used in malaria therapy for over 70 years, prevented infection with Nipah virus in vitro. Chloroquine was assessed using a ferret model of lethal Nipah virus infection and found to be ineffective against Nipah virus infection in vivo.

Download Full-text

in silico Docking Analysis of Small Molecule Inhibitors from Nyctanthes arbor-tristis against Nipah Virus Infection

Asian Journal of Organic & Medicinal Chemistry ◽

10.14233/ajomc.2019.ajomc-p235 ◽

2019 ◽

Vol 4 (4) ◽

pp. 244-247

Author(s):

Nayana Mohan ◽

V. Meera ◽

J. Soja ◽

M.S. Latha

Keyword(s):

Virus Infection ◽

Early Stage ◽

Nipah Virus ◽

Docking Simulation ◽

Severe Illness ◽

Highly Pathogenic ◽

Docking Analysis ◽

Computational Docking ◽

In Silico Docking ◽

Biosafety Level

Nipah virus is a highly pathogenic paramyxovirus belonging to the genus Henipavirus, classified as Biosafety Level 4 (BSL4) agents. The virus causes severe illness characterized by encephalitis or respiratory disease in human. The case-lethality rate of Nipah was reported to be 70 % in India, since year 2001. Despite the high pathogenicity of virus, no therapeutics are currently approved for use in human. But, ribavirin, favipiravir and human mono clonal antibody was found to reduce the intensity in early stage. Medicinal plants serve as a rich source of therapeutically active compounds. Nyctanthus arbortristis Linn or pavizhamalli (Harsinger) is traditionally known to have activity against Nipha virus. In this study, therapeutic activity of phytochemicals arbortristoside A and arbortristoside C present in pavizhamalli plant against Nipha virus target was investigated by computational docking simulation. Computational docking analysis was performed using Schrodinger Suite. The phytochemicals arbortristoside A and arbortristoside C show promising binding affinity with the target Nipah virus than the reference drugs. Results of the study could be advantageous to develop a new lead molecule against Nipah virus infection.

Download Full-text

SARS-CoV-2 receptor binding domain fusion protein efficiently neutralizes virus infection

PLoS Pathogens ◽

10.1371/journal.ppat.1010175 ◽

2021 ◽

Vol 17 (12) ◽

pp. e1010175

Author(s):

Abigael Eva Chaouat ◽

Hagit Achdout ◽

Inbal Kol ◽

Orit Berhani ◽

Gil Roi ◽

...

Keyword(s):

Virus Infection ◽

Enzymatic Activity ◽

Receptor Binding ◽

Viral Entry ◽

Surface Expression ◽

Binding Domain ◽

Host Cells ◽

Receptor Binding Domain ◽

High Virus

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Currently, as dangerous mutations emerge, there is an increased demand for specific treatments for SARS-CoV-2 infected patients. The spike glycoprotein on the virus membrane binds to the angiotensin converting enzyme 2) ACE2 (receptor on host cells through its receptor binding domain (RBD) to mediate virus entry. Thus, blocking this interaction may inhibit viral entry and consequently stop infection. Here, we generated fusion proteins composed of the extracellular portions of ACE2 and RBD fused to the Fc portion of human IgG1 (ACE2-Ig and RBD-Ig, respectively). We demonstrate that ACE2-Ig is enzymatically active and that it can be recognized by the SARS-CoV-2 RBD, independently of its enzymatic activity. We further show that RBD-Ig efficiently inhibits in-vivo SARS-CoV-2 infection better than ACE2-Ig. Mechanistically, we show that anti-spike antibody generation, ACE2 enzymatic activity, and ACE2 surface expression were not affected by RBD-Ig. Finally, we show that RBD-Ig is more efficient than ACE2-Ig at neutralizing high virus titers. We thus propose that RBD-Ig physically blocks virus infection by binding to ACE2 and that RBD-Ig should be used for the treatment of SARS-CoV-2-infected patients.

Download Full-text

O.46 Whole body protein turnover assessed with leucine and glutamine kinetics in vivo at an early stage of human immunodeficiency virus infection

Clinical Nutrition ◽

10.1016/s0261-5614(96)80093-8 ◽

1996 ◽

Vol 15 ◽

pp. 13 ◽

Cited By ~ 2

Author(s):

B. Rakotoambinina ◽

J.J. Raynaud ◽

J.C. Melchior ◽

P. Crenn ◽

F. Thuillier ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Infection ◽

Human Immunodeficiency Virus Infection ◽

Protein Turnover ◽

Early Stage ◽

Whole Body ◽

Body Protein ◽

Immunodeficiency Virus ◽

Kinetics In Vivo

Download Full-text

Rousettus aegyptiacus Bats Do Not Support Productive Nipah Virus Replication

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz429 ◽

2019 ◽

Vol 221 (Supplement_4) ◽

pp. S407-S413 ◽

Cited By ~ 2

Author(s):

Stephanie N Seifert ◽

Michael C Letko ◽

Trenton Bushmaker ◽

Eric D Laing ◽

Greg Saturday ◽

...

Keyword(s):

Respiratory Distress ◽

Cell Lines ◽

Virus Replication ◽

Viral Entry ◽

Nipah Virus ◽

Model Organism ◽

Severe Respiratory Distress ◽

Zoonotic Pathogen ◽

Fruit Bat

Abstract Nipah virus (NiV) is a bat-borne zoonotic pathogen that can cause severe respiratory distress and encephalitis upon spillover into humans. NiV is capable of infecting a broad range of hosts including humans, pigs, ferrets, dogs, cats, hamsters, and at least 2 genera of bats. Little is known about the biology of NiV in the bat reservoir. In this study, we evaluate the potential for the Egyptian fruit bat (EFB), Rousettus aegyptiacus, to serve as a model organism for studying NiV in bats. Our data suggest that NiV does not efficiently replicate in EFBs in vivo. Furthermore, we show no seroconversion against NiV glycoprotein and a lack of viral replication in primary and immortalized EFB-derived cell lines. Our data show that despite using a conserved target for viral entry, NiV replication is limited in some bat species. We conclude that EFBs are not an appropriate organism to model NiV infection or transmission in bats.

Download Full-text

Multi-Omics Sequencing Provides Insights Into Age-Dependent Susceptibility of Grass Carp (Ctenopharyngodon idellus) to Reovirus

Frontiers in Immunology ◽

10.3389/fimmu.2021.694965 ◽

2021 ◽

Vol 12 ◽

Author(s):

Libo He ◽

Denghui Zhu ◽

Xinyu Liang ◽

Yongming Li ◽

Lanjie Liao ◽

...

Keyword(s):

Virus Infection ◽

Grass Carp ◽

Early Stage ◽

Nucleotide Metabolism ◽

Hemorrhagic Disease ◽

Ctenopharyngodon Idellus ◽

Intergroup Comparison ◽

Age Dependent

Grass carp (Ctenopharyngodon idellus) is an important aquaculture species in China that is affected by serious diseases, especially hemorrhagic disease caused by grass carp reovirus (GCRV). Grass carp have previously shown age-dependent susceptibility to GCRV, however, the mechanism by which this occurs remains poorly understood. Therefore, we performed transcriptome and metabolome sequencing on five-month-old (FMO) and three-year-old (TYO) grass carp to identify the potential mechanism. Viral challenge experiments showed that FMO fish were susceptible, whereas TYO fish were resistant to GCRV. RNA-seq showed that the genes involved in immune response, antigen presentation, and phagocytosis were significantly upregulated in TYO fish before the GCRV infection and at the early stage of infection. Metabolome sequencing showed that most metabolites were upregulated in TYO fish and downregulated in FMO fish after virus infection. Intragroup analysis showed that arachidonic acid metabolism was the most significantly upregulated pathway in TYO fish, whereas choline metabolism in cancer and glycerophospholispid metabolism were significantly downregulated in FMO fish after virus infection. Intergroup comparison revealed that metabolites from carbohydrate, amino acid, glycerophospholipid, and nucleotide metabolism were upregulated in TYO fish when compared with FMO fish. Moreover, the significantly differentially expressed metabolites showed antiviral effects both in vivo and in vitro. Based on these results, we concluded that the immune system and host biosynthesis and metabolism, can explain the age-dependent viral susceptibility in grass carp.

Download Full-text

A Cross-Reactive Humanized Monoclonal Antibody Targeting Fusion Glycoprotein Function Protects Ferrets Against Lethal Nipah Virus and Hendra Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz515 ◽

2019 ◽

Vol 221 (Supplement_4) ◽

pp. S471-S479 ◽

Cited By ~ 5

Author(s):

Chad E Mire ◽

Yee-Peng Chan ◽

Viktoriya Borisevich ◽

Robert W Cross ◽

Lianying Yan ◽

...

Keyword(s):

Monoclonal Antibody ◽

Virus Infection ◽

Severe Disease ◽

Human Monoclonal Antibody ◽

Nipah Virus ◽

Antibody Therapy ◽

Hendra Virus ◽

High Dose ◽

Virus Challenge

Abstract Background Nipah virus (NiV) and Hendra virus (HeV) are zoonotic paramyxoviruses that cause severe disease in both animals and humans. There are no approved vaccines or treatments for use in humans; however, therapeutic treatment of both NiV and HeV infection in ferrets and non-human primates with a cross-reactive, neutralizing human monoclonal antibody (mAb), m102.4, targeting the G glycoprotein has been demonstrated. In a previous study, we isolated, characterized, and humanized a cross-reactive, neutralizing anti-F mAb (h5B3.1). The mAb h5B3.1 blocks the required F conformational change needed to facilitate membrane fusion and virus infection, and the epitope recognized by h5B3.1 has been structurally defined; however, the efficacy of h5B3.1 in vivo is unknown. Methods The post-infection antiviral activity of h5B3.1 was evaluated in vivo by administration in ferrets after NiV and HeV virus challenge. Results All subjects that received h5B3.1 from 1 to several days after infection with a high-dose, oral-nasal virus challenge were protected from disease, whereas all controls died. Conclusions This is the first successful post-exposure antibody therapy for NiV and HeV using a humanized cross-reactive mAb targeting the F glycoprotein, and the findings suggest that a combination therapy targeting both F and G should be evaluated as a therapy for NiV/HeV infection.

Download Full-text

HIV-1 accessory protein Vpr interacts with REAF/RPRD2 to mitigate its antiviral activity

10.1101/408161 ◽

2018 ◽

Cited By ~ 2

Author(s):

Joseph M Gibbons ◽

Kelly M Marno ◽

Rebecca Pike ◽

Wing-yiu Jason Lee ◽

Christopher E Jones ◽

...

Keyword(s):

T Cells ◽

Viral Replication ◽

Viral Entry ◽

Reverse Transcription ◽

Early Phase ◽

Early Stage ◽

Target Cells ◽

Accessory Protein ◽

Hiv 1

AbstractThe Human Immunodeficiency Virus type 1 (HIV-1) accessory protein Vpr enhances viral replication in both macrophages and in cycling T cells to a lesser extent. Virion packaged Vpr is released in target cells shortly after entry, suggesting its requirement in the early phase of infection. Previously, we described REAF (RNA-associated Early-stage Antiviral Factor, RPRD2), a constitutively expressed protein that potently restricts HIV replication at or during reverse transcription. Here, we show that a virus without intactvpris more highly restricted by REAF and, using delivery by VLPs, that Vpr alone is sufficient for REAF degradation in primary macrophages. REAF is more highly expressed in macrophages than in cycling T cells and we detect, by co-immunoprecipitation assay, an interaction between Vpr protein and endogenous REAF. Vpr acts very quickly during the early phase of replication and induces the degradation of REAF within 30 minutes of viral entry. Using Vpr F34I and Q65R viral mutants, we show that nuclear localisation and interaction with cullin4A-DBB1 (DCAF1) E3 ubiquitin ligase is required for REAF degradation by Vpr. In response to infection, cells upregulate REAF levels. This response is curtailed in the presence of Vpr. These findings support the hypothesis that Vpr induces the degradation of a factor, REAF, which impedes HIV infection in macrophages.ImportanceFor at least 30 years, it has been known that HIV-1 Vpr, a protein carried in the virion, is important for efficient infection of primary macrophages. Vpr is also a determinant of the pathogenic effects of HIV-1in vivo. A number of cellular proteins that interact with Vpr have been identified. So far, it has not been possible to associate these proteins with altered viral replication in macrophages, or to explain why Vpr is carried in the virus particle. Here we show that Vpr mitigates the antiviral effects of REAF, a protein highly expressed in primary macrophages and one which inhibits virus replication early during reverse transcription. REAF is degraded by Vpr within 30 minutes of virus entry, in a manner dependent on the nuclear localization of Vpr and its interaction with the cell’s protein degradation machinery.

Download Full-text