Current and future antiviral therapy of severe seasonal and avian influenza

John Beigel, Mike Bray, John Beigel, Mike Bray

Abstract

The currently circulating H3N2 and H1N1 subtypes of influenza A virus cause a transient, febrile upper respiratory illness in most adults and children ("seasonal influenza"), but infants, the elderly, immunodeficient and chronically ill persons may develop life-threatening primary viral pneumonia or complications such as bacterial pneumonia. By contrast, avian influenza viruses such as the H5N1 virus that recently emerged in Southeast Asia can cause severe disease when transferred from domestic poultry to previously healthy people ("avian influenza"). Most H5N1 patients present with fever, cough and shortness of breath that progress rapidly to adult respiratory distress syndrome. In seasonal influenza, viral replication remains confined to the respiratory tract, but limited studies indicate that H5N1 infections are characterized by systemic viral dissemination, high cytokine levels and multiorgan failure. Gastrointestinal infection and encephalitis also occur. The licensed anti-influenza drugs (the M2 ion channel blockers, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir) are beneficial for uncomplicated seasonal influenza, but appropriate dosing regimens for severe seasonal or H5N1 viral infections have not been defined. Treatment options may be limited by the rapid emergence of drug-resistant viruses. Ribavirin has also been used to a limited extent to treat influenza. This article reviews licensed drugs and treatments under development, including high-dose oseltamivir; parenterally administered neuraminidase inhibitors, peramivir and zanamivir; dimeric forms of zanamivir; the RNA polymerase inhibitor T-705; a ribavirin prodrug, viramidine; polyvalent and monoclonal antibodies; and combination therapies.

Figures

Fig. 1
Fig. 1
The influenza A virus replication cycle. The virion core contains eight RNA genome segments encapsidated by nucleoprotein (RNPs) and embedded together with associated polymerase (P) molecules in a matrix of M1 proteins. After binding to sialic acid–galactose linked to a cell-surface glycoprotein or glycolipid, the virion is taken up in an endocytic vesicle, where acidification triggers a conformational change that bring viral and endosomal membranes together. Acidification also produces a flow of protons through the M2 ion channel into the interior of the virion, causing the RNPs to dissociate from the M1 matrix and be released into the cytoplasm. They are then transported to the nucleus, where a viral polymerase complex performs transcription and genome replication. The resulting mRNAs move to the cytoplasm and are translated, producing new RNP protein components that are transported back to the nucleus to associate with nascent genome segments. The exit of new RNPs from the nucleus is aided by the viral NS2 (nuclear export protein, NEP). Meanwhile, nascent HA, NA and M2 molecules pass through the Golgi apparatus and undergo glycosylation before moving to the cell membrane. HA is also cleaved to form two chains linked by a disulfide bond. Virion assembly occurs as RNPs and M1 proteins associate with cytoplasmic tails of HA and NA. Successful release of new virus particles requires that NA cleave sialic acid from galactose on the cell surface or on adjacent virions to prevent HA binding.
Fig. 2
Fig. 2
Licensed antivirals that block the influenza A M2 ion channel: amantadine (A); rimantadine (B) (Courtesy of Pieter Leyssen).
Fig. 3
Fig. 3
The structure of N-acetylneuraminic (sialic) acid (A) and antiviral drugs that compete with it for the active site of the influenza A or B neuraminidase: oseltamivir (B); zanamivir (C); peramivir (D) (Courtesy of Pieter Leyssen).
Fig. 4
Fig. 4
Nucleoside analogues that interfere with influenza virus RNA polymerase function: ribavirin (A); viramidine (B); T-705 (C) (Courtesy of Pieter Leyssen).

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