ANTIVIRAL RESISTANCE AND INFLUENZA VIRUS FITNESS
FIGURE: Resistance to the neuraminidase (NA) inhibitor oseltamivir is conferred by a single point mutation in the NA enzyme active site. (Left) Ribbon structure of the tetrameric NA from the oseltamivir-resistant clinical isolate influenza A/New York/08-1326/2008 (H1N1). (Right) The active site of NY/08-1326. Catalytic residues are colored orange, and framework residues are colored yellow. The resistance mutation H275Y is highlighted in purple.
Into the early 2000s, it was assumed that neuraminidase inhibitor (NAI)-resistant influenza viruses would be clinically irrelevant; amino acid mutations conferring NAI resistance were thought to be too costly to viral fitness. This prediction was proved wrong between 2007 and 2009, when virtually all seasonal influenza A(H1N1) (“sH1N1”) viruses, typified by the vaccine strain A/Brisbane/59/2007 (H1N1) (“Bris/59”), became resistant to the neuraminidase (NA) inhibitor oseltamivir.
We hypothesized that the oseltamivir-resistant NA conferred a fitness advantage — specifically, more efficient transmissibility — upon Bris/59-like sH1N1 viruses, thus explaining the rapidity with which viruses encoding an oseltamivir-resistant NA replaced earlier strains encoding a sensitive NA.
We performed a series of transmission experiments in the guinea pig model with the Bris/59-like clinical isolates A/NY/08-1253/2008 (H1N1) (oseltamivir-sensitive), A/NY/08-1326/2008 (H1N1) (oseltamivir-resistant), and reverse genetics- (rg-) derived reassortants of the two.
FIGURE: Guinea pig transmission of A/Brisbane/59/2007-like seasonal influenza A(H1N1) viruses is enhanced by expression of an oseltamivir-resistant neuraminidase. The label “(R)” indicates viruses with an oseltamivir-resistant NA, and “(S)” indicates viruses with an oseltamivir-sensitive NA. **, p < 0.01. by the log-rank test.
A Kaplan-Meier time-to-event analysis of data reported previously [Bouvier et al., Journal of Virology 2012 Jul; 86(13): 7268-79] demonstrates that, collectively, Bris/59-like viruses encoding an oseltamivir-resistant NA — including an rg-derived 7:1 reassortant encoding the resistant NA, expressed in the context of the remaining seven segments from the oseltamivir-sensitive isolate, and a 6:2 reassortant encoding both the hemagglutinin (HA) and the NA from the resistant virus, in a backbone of the sensitive isolate — transmitted significantly more rapidly than did viruses encoding the oseltamivir-sensitive Bris/59 NA or a Bris/59-like NA.
Overall, with this research and prior work, we have demonstrated that “viral fitness” is a polygenic trait, and context-dependent compensatory mutations can evolve to restore efficient mammalian transmissibility to oseltamivir-resistant viruses.
Hai R, Schmolke M, Leyva-Grado VH, Thangavel RR, Margine I, Jaffe EL, Krammer F, Solórzano A, García-Sastre A, Palese P, Bouvier NM. Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nature Communications 2013 Dec 10; 4: 2854.
Bouvier NM, Rahmat S, Pica N. Enhanced mammalian transmissibility of seasonal Influenza A/H1N1 viruses encoding an oseltamivir-resistant neuraminidase. Journal of Virology 2012 Jul; 86(13): 7268-79.
Seibert CW, Rahmat S, Krammer F, Palese P, Bouvier NM. Efficient transmission of pandemic H1N1 influenza viruses with high-level oseltamivir resistance. Journal of Virology 2012 May; 86(9): 5386-9.
Bouvier NM, Lowen AC, Palese P. Oseltamivir-resistant influenza A viruses are transmitted efficiently among guinea pigs by direct contact but not by aerosol. Journal of Virology 2008 Oct; 82(20):10052-8. —
ENVIRONMENTAL FACTORS AFFECTING INFLUENZA VIRUS TRANSMISSION
FIGURE: Environmental Modulation of Respiratory Virus Transmission.
Transmission of respiratory viruses depends upon a complex chain of events occurring between infected and susceptible hosts, including naturally infected humans and experimentally inoculated animal models such as guinea pigs and ferrets. Environmental factors such as temperature, humidity, weather, and ventilation are hypothesized to have an impact on various aspects of the transmission chain.
Pica N, Bouvier NM. Ambient Temperature and Respiratory Virus Infection. Pediatric Infectious Diseases Journal 2014 Mar; 33(3): 311-3.