Influenza A virus uses Cell Biology to maximize viral fitness

JAVIER G. MAGADAN; JACK R. BENNINK; JONATHAN W. YEWDELL

Saxtons River, Vermont

Conferencia; "From Unfolded Proteins in the ER to Disease" FASEB Science Research Conference; 2015

FASEB

Influenza viruses spread around the world causing seasonal epidemics, resulting in about 3 to 5 million infections and 250,000 to 500,000 deaths annually, and also sporadic pandemics, which have historically occurred every 10-40 years. The continued threat of influenza viruses in the human population is associated with its ability to escape protective immunity, to be transmitted through respiratory droplets, and the frequent emergence of antigenically novel viral strains from avian and non-avian animal reservoirs. Given the large public health and economical burden due to circulating influenza viruses, their 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 (exposure to anti-HA neutralizing antibodies), 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. Consistent with this observation, 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. Our observations are original and important in several ways: 1) they suggest a previously uncovered, multilayered mechanism, by which drifted IAVs not only maximize viral fitness compensating glycoprotein activity but also acquire drug resistance; 2) in addition, our comprehensively characterization of the cellular pathways and critical factors involved in the maturation and trafficking of NA undoubtedly offers an excellent opportunity for discovering potential therapeutic targets