Influenza A virus uses Cell Biology to maximize viral fitness

JAVIER G. MAGADAN

La Serena

Workshop; "Actualizations in Membrane Trafficking in Health and Disease" EMBO Workshop; 2016

EMBO

Influenza viruses spread around the world causing both seasonal epidemics and sporadic pandemics. The continued threat of influenza viruses in the human population is associated with their ability to escape protective immunity and the frequent emergence of antigenically novel strains from avian and non-avian animal reservoirs. Thus, influenza´s improved control through effective anti-viral strategies and efficient immunization protocols is immediately needed. However, the performance of new-released therapeutic and preventive approaches is usually compromised due to the rapid acquisition of amino acid substitutions in two viral surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). This phenomenon, also known as "antigenic drift", allows influenza viruses to evade adverse conditions that may affect their proper replication and propagation, like the host immune humoral response and anti-viral therapies. Despite of their beneficial outcome, mutations that affect HA or NA functions can also drastically impair viral fitness. Due to HA and NA opposite functions during the viral life cycle, influenza viruses frequently incorporate secondary or "compensatory" changes in one or another glycoprotein in order to maintain in equilibrium the delicate HA/NA balance and thus maximize viral replication. Our results indicate that under certain conditions of selective pressure, influenza A virus (IAV) compensates harmful mutations in HA by incorporate new amino acid substitutions in NA, which not only leads to anti-viral drug resistance but also impairs NA incorporation into nascent virus particles, and by inference, NA activity per virion. We also found that such mutations in NA have a profound impact at the host level, mainly affecting NA conformation stability and its intracellular trafficking from the endoplasmic reticulum (ER) to the plasma membrane, the primary place where the new viral progeny is assembled. These results uncover a new multilayered mechanism, by which drifted IAVs not only maximize viral fitness compensating glycoprotein activity but also acquire drug resistance