Knowns and Unknowns of Influenza B Viruses

Koutsakos, Marios; Nguyen, Thi H. O.; Barclay, William; Kedzierska, Katherine

doi:10.2217/fmb.15.120

Cited by 99 publications

(101 citation statements)

References 149 publications

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“…Two types of influenza viruses, A and B, are responsible for the seasonal flu. On average influenza A infections are more common in the seasonal flu 1 , but the influenza B virus becomes dominant in the spring months, and in some seasons can account for up to 50% of infections (data available from CDC FluView, www.cdc.gov/flu/weekly/) 2 .…”

Section: Introductionmentioning

confidence: 99%

Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel

et al. 2016

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Together with the influenza A virus, influenza B virus causes seasonal flu epidemics. The M2 protein of influenza B (BM2) forms a tetrameric proton-conducting channel that is important for the virus lifecycle. BM2 shares little sequence homology with AM2, except for a conserved HxxxW motif in the transmembrane (TM) domain. Unlike AM2, no antiviral drugs have been developed to block the BM2 channel. To elucidate the proton-conduction mechanism of BM2 and to facilitate the development of BM2 inhibitors, we have employed solid-state NMR spectroscopy to investigate the conformation, dynamics and hydration of the BM2 TM domain in lipid bilayers. BM2 adopts an α-helical conformation in lipid membranes. At physiological temperature and low pH, the proton-selective residue, His19, shows relatively narrow 15N chemical exchange peaks for the imidazole nitrogens, indicating fast proton shuttling that interconverts cationic and neutral histidines. Importantly, pH-dependent 15N chemical shifts indicate that His19 retains the neutral population to much lower pH than His37 in AM2, indicating larger acid-dissociation constants or lower pKa’s. We attribute these dynamical and equilibrium differences to the presence of a second titratable histidine, His27, which may increase the proton-dissociation rate of His19. 2D 1H-13C correlation spectra probing water 1H polarization transfer to the peptide indicates that the BM2 channel becomes much more hydrated at low pH than at high pH, particularly at Ser12, indicating that the pore-facing serine residues in BM2 mediate proton relay to the proton-selective histidine.

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Section: Introductionmentioning

confidence: 99%

Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel

et al. 2016

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“…Besides influenza A viruses, influenza B viruses are also substantial human pathogens. Infection with influenza B viruses can be as severe as influenza A viruses, especially in children and immunocompromised patients (Koutsakos et al, 2016). Influenza A and B viruses co-circulate in each influenza season, and as a result, both the trivalent and quadrivalent influenza vaccines contain the viral components from influenza B viruses.…”

Section: Introductionmentioning

confidence: 99%

Discovery of dapivirine, a nonnucleoside HIV-1 reverse transcriptase inhibitor, as a broad-spectrum antiviral against both influenza A and B viruses

Zhang

Musharrafieh

et al. 2017

Antiviral Research

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The emergence of multidrug-resistant influenza viruses poses a persistent threat to public health. The current prophylaxis and therapeutic interventions for influenza virus infection have limited efficacy due to the continuous antigenic drift and antigenic shift of influenza viruses. As part of our ongoing effort to develop the next generation of influenza antivirals with broad-spectrum antiviral activity and a high genetic barrier to drug resistance, in this study we report the discovery of dapivirine, an FDA-approved HIV nonnucleoside reverse transcriptase inhibitor, as a broad-spectrum antiviral against multiple strains of influenza A and B viruses with low micromolar efficacy. Mechanistic studies revealed that dapivirine inhibits the nuclear entry of viral ribonucleoproteins at the early stage of viral replication. As a result, viral RNA and protein synthesis were inhibited. Furthermore, dapivirine has a high in vitro genetic barrier to drug resistance, and its antiviral activity is synergistic with oseltamivir carboxylate. In summary, the in vitro antiviral results of dapivirine suggest it is a promising candidate for the development of the next generation of dual influenza and HIV antivirals.

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“…a result, influenza B virus has not been seen to present the same level of public threat, because it does not pose the same pandemic risk as influenza A (7,(9)(10)(11).…”

mentioning

confidence: 99%

“…Complications of influenza B include secondary bacterial pneumonias, myocarditis, neurologic and muscular complications, encephalitis, and death (7,16). Disease severity from influenza B appears to be highest in children and adolescents (4,7,11,15), and mortality from influenza B is higher than that from influenza A in hospitalized children (11).…”

mentioning

confidence: 99%

“…A membraneenveloped RNA virus, influenza B virus, like influenza A virus, expresses two immunodominant surface proteins, hemagglutinin (HA) and neuraminidase. HA is essential for viral attachment, entry, and fusion with host cell membranes; most neutralizing antibodies in an immune response target the receptor-binding head region of HA (7). Genetic drift and significant sequence diversity in the HA genes within various lineages of influenza B virus limit the ability of these antibodies to broadly protect against influenza B infection (16).…”

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confidence: 99%

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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

Lim¹,

Derby²,

Zhang³

et al. 2017

Antimicrob Agents Chemother

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Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascendingdose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of Ͼ18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time-or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.)

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Knowns and Unknowns of Influenza B Viruses

Cited by 99 publications

References 149 publications

Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel

Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel

Discovery of dapivirine, a nonnucleoside HIV-1 reverse transcriptase inhibitor, as a broad-spectrum antiviral against both influenza A and B viruses

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

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