Recent work suggests that the origin of both the fitness reduction conferred by the H275Y mutation and the unique fitness of the A/Brisbane/59/2007 mutant strain is found in the virus NA activity and surface expression. Specifically, the reduction of NA activity conferred by the H275Y mutation has been associated with a reduced expression of surface neuraminidase, possibly due to defects in the folding of the molecule or its transport through the cellular membrane [24] . It has been shown, however, that two other mutations in the NA gene (V234M and R222Q) can provide a compensatory effect by increasing NA surface expression, and that these two substitutions indeed occurred in the evolution of the H1N1 seasonal strain between 1999 and 2007 [24] . The neuraminidase of contemporary (A/Brisbane/59/2007-like) strains susceptible to oseltamivir have shown a higher affinity for the substrate in NA activity assays than older H1N1 seasonal strains (e.g., A/New Caledonia/20/99 and A/Solomon Islands/3/06); contemporary oseltamivir-resistant strains (with the H275Y substitution) have shown a decrease in that affinity, but remain above the level of older strains [25] . Thus, it seems that these pre-existing mutations led to an over-expression of NA and provided a favorable environment for the appearance of the H275Y mutation. The eventual dominance of the H275Y mutant may be due to a better balance between the hemagglutinin (HA) and NA activity [25, 26] . It remains an open question, however, precisely how these mechanistic changes lead to viral fitness changes. The answer to this should be found in the details of the infection kinetics in the interaction of virus and cell.