Last data update: Jul 01, 2024. (Total: 47134 publications since 2009)
Records 1-5 (of 5 Records) |
Query Trace: Hotard AL [original query] |
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A respiratory syncytial virus attachment (G) gene variant associated with more severe disease in infants decreases fusion (F) protein expression which may facilitate immune evasion.
Human S , Hotard AL , Rostad CA , Lee S , McCormick L , Larkin EK , Peret TCT , Jorba J , Lanzone J , Gebretsadik T , Williams JV , Bloodworth M , Stier M , Carroll K , Peebles RS Jr , Anderson LJ , Hartert TV , Moore ML . J Virol 2020 95 (2) ![]() ![]() This study identified a genotype of RSV associated with increased acute respiratory disease severity in a cohort of term, previously healthy infants. The genotype (2stop+A4G) consists of two components. The A4G component is a prevalent point mutation in the 4(th) position of the gene end transcription termination signal of the G gene of currently circulating RSV strains. The 2stop component is two tandem stop codons at the G gene terminus, preceding the gene end transcription termination signal. To investigate the biological role of these RSV G gene mutations, recombinant RSV strains harboring either a wild type A2 strain G gene (one stop codon preceding a wild type gene end signal), an A4G gene end signal preceded by one stop codon, or the 2stop+A4G virulence-associated combination were generated and characterized. Infection with the rA4G RSV mutant resulted in transcriptional read-through and lower G and fusion (F) protein levels relative to wild type. Addition of a second stop codon preceding the A4G point mutation (2stop+A4G) restored G protein expression but retained lower F protein levels. These data suggest that RSV G and F glycoprotein expression is regulated by transcriptional and translational read-through. Notably, while rA4G and r2stop+A4G RSV were attenuated in cells and in naïve BALB/c mice compared to wild type RSV, the r2stop+A4G RSV was better able to infect BALB/c mice in the presence of pre-existing immunity in comparison to rA4G RSV. Together these factors may contribute to the maintenance and virulence of the 2stop+A4G genotype in currently circulating RSV-A strains.IMPORTANCE Strain-specific differences in respiratory syncytial virus (RSV) isolates are associated with differential pathogenesis in mice. However, the role of RSV genotypes in human infection is incompletely understood. This work demonstrates that one such genotype, 2stop+A4G, present in the RSV attachment (G) gene terminus is associated with greater infant disease severity. The genotype consists of two tandem stop codons preceding an A-to-G point mutation in the 4(th) position of the G gene end transcription termination signal. Virologically, the 2stop+A4G RSV genotype results in reduced levels of the RSV fusion (F) glycoprotein. A recombinant 2stop+A4G RSV was better able to establish infection in the presence of existing RSV immunity compared to a virus harboring the common A4G mutation. These data suggest that regulation of G and F expression has implications for virulence and potentially immune evasion. |
Griffithsin inhibits Nipah virus entry and fusion and can protect Syrian golden hamsters from lethal Nipah virus challenge
Lo MK , Spengler JR , Krumpe LRH , Welch SR , Chattopadhyay A , Harmon JR , Coleman-McCray JD , Scholte FEM , Hotard AL , Fuqua JL , Rose JK , Nichol ST , Palmer KE , O'Keefe BR , Spiropoulou CF . J Infect Dis 2020 221 S480-S492 Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis and respiratory disease in humans. There is currently no approved therapeutic for human use against NiV infection. Griffithsin (GRFT) is high-mannose oligosaccharide binding lectin that has shown in vivo broad-spectrum activity against viruses including severe acute respiratory syndrome coronavirus, human immunodeficiency virus 1, hepatitis C virus, and Japanese encephalitis virus. In this study, we evaluated the in vitro antiviral activities of GRFT and its synthetic trimeric tandemer (3mG) against NiV and other viruses from across 4 virus families. The 3mG had comparatively greater potency than GRFT against NiV due to its enhanced ability to block NiV glycoprotein-induced syncytia formation. Our initial in vivo prophylactic evaluation of an oxidation-resistant GRFT (Q-GRFT) showed significant protection against lethal NiV challenge in Syrian golden hamsters. Our results warrant further development of Q-GRFT and 3mG as potential NiV therapeutics. |
A conserved basic patch and central kink in the Nipah virus phosphoprotein multimerization domain are essential for polymerase function
Bruhn JF , Hotard AL , Spiropoulou CF , Lo MK , Saphire EO . Structure 2019 27 (4) 660-668 e4 Nipah virus is a highly lethal zoonotic pathogen found in Southeast Asia that has caused human encephalitis outbreaks with 40%-70% mortality. NiV encodes its own RNA-dependent RNA polymerase within the large protein, L. Efficient polymerase activity requires the phosphoprotein, P, which tethers L to its template, the viral nucleocapsid. P is a multifunctional protein with modular domains. The central P multimerization domain is composed of a long, tetrameric coiled coil. We investigated the importance of structural features found in this domain for polymerase function using a newly constructed NiV bicistronic minigenome assay. We identified a conserved basic patch and central kink in the coiled coil that are important for polymerase function, with R555 being absolutely essential. This basic patch and central kink are conserved in the related human pathogens measles and mumps viruses, suggesting that this mechanism may be conserved. |
4'-Azidocytidine (R1479) inhibits henipaviruses and other paramyxoviruses with high potency
Hotard AL , He B , Nichol ST , Spiropoulou CF , Lo MK . Antiviral Res 2017 144 147-152 The henipaviruses Nipah virus and Hendra virus are highly pathogenic zoonotic paramyxoviruses which have caused fatal outbreaks of encephalitis and respiratory disease in humans. Despite the availability of a licensed equine Hendra virus vaccine and a neutralizing monoclonal antibody shown to be efficacious against henipavirus infections in non-human primates, there remains no approved therapeutics or vaccines for human use. To explore the possibility of developing small-molecule nucleoside inhibitors against henipaviruses, we evaluated the antiviral activity of 4'-azidocytidine (R1479), a drug previously identified to inhibit flaviviruses, against henipaviruses along with other representative members of the family Paramyxoviridae. We observed similar levels of R1479 antiviral activity across the family, regardless of virus genus. Our brief study expands the documented range of viruses susceptible to R1479, and provides the basis for future investigation and development of 4'-modified nucleoside analogs as potential broad-spectrum antiviral therapeutics across both positive and negative-sense RNA virus families. |
GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses
Lo MK , Jordan R , Arvey A , Sudhamsu J , Shrivastava-Ranjan P , Hotard AL , Flint M , McMullan LK , Siegel D , Clarke MO , Mackman RL , Hui HC , Perron M , Ray AS , Cihlar T , Nichol ST , Spiropoulou CF . Sci Rep 2017 7 43395 GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern. |
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