INFLUENZA HEMAGGLUTININ H3

Influenza hemagglutinin H3

Influenza hemagglutinin H3

Influenza virus neuraminidase inhibitor (NI) resistance is defined as a significantly raised IC50 (drug concentration inhibiting neuraminidase (NA) activity by 50%) value, coupled with a characterised mutation in the NA gene. The table below shows the NAI resistance mutations that have been generated and classified in vitro. Susceptibility to NI drugs is not absolute, ranging from an alteration in susceptibility to full resistance. There are typical ranges of IC50 values that differ between influenza subtypes and between oseltamivir and zanamivir for each subtype. It is not, therefore, possible to compare subtype and drug specific data. Influenza B viruses tend to have IC50 values 10-100 fold higher than influenza A viruses. This is normal for influenza B and this lower susceptibility does not appear to have a significant clinical impact. IC50 values for influenza B viruses tend to be higher for oseltamivir than zanamivir. IC50 values for H1N1 viruses tend to be higher for zanamivir than oseltamivir, whereas the inverse is true for H3N2 viruses where IC50 values tend to be higher for oseltamivir than zanamivir. Furthermore, values generated by fluorescence and chemiluminescence methods should not be compared as values generated by chemiluminescence are typically lower than those for the same virus and drug in the fluorescence test. IC50 values generated from the different assay methods should not be directly compared. (NICHOLLS, 149).

Although the influenza H3 hemagglutinin has been chosen as the paradigm, since so much is known, there are 16 subtypes of influenza HA (H1-H16), defined by lack of antigenic cross-reactivity. There is typically only about 20% amino acid sequence identity between HAs of different subtypes. There are interesting and important differences in how easily a particular strain within the subtype can change its binding specificity between avian-like and human-like receptors, leading to the failure so far of H5N1 to be established in the human population, whereas swine-origin H1N1 showed high transmissibility between humans from the time it was first isolated (NICHOLLS, 149).

To understand the transmission of influenza viruses and how new pandemics begin, it will be important to study a variety of HA subtypes and strains. but for other subtypes the precise rules may differ. However, much progress had been made in the CFG with participating investigators of understanding the receptor specificity and transmissibility of H1 and H2 subtypes. Fortunately, the H5N1 avian virus has still not acquired the ability to transmit between humans, as the rules seem more complex compared to H1, H2 and H3, despite at least 15 years of opportunity. The CFG has facilitated considerable advances in our knowledge of the role of sialic acid binding in influenza host specificity and tropism for the upper or lower respiratory tract, and these studies need to be continued until we understand how influenza viruses enter the human population to cause each new pandemic, and the role of receptor specificity in pathogen city.

CFG Participating Investigators (PIs) contributing to the understanding of H3 include: Gillian Air, Rafi Ahmed, Nicolai Bovin, Ruben ...