Quantifying the fitness advantage of polymerase substitutions in Influenza A/H7N9 viruses during adaptation to humans.

Adaptation of zoonotic influenza viruses towards efficient human-to-human transmissibility is a substantial public health concern. The recently emerged A/H7N9 influenza viruses in China provide an opportunity for quantitative studies of host-adaptation, as human-adaptive substitutions in the PB2 gene of the virus have been found in all sequenced human strains, while these substitutions have not been detected in any non-human A/H7N9 sequences. Given the currently available information, this observation suggests that the human-adaptive PB2 substitution might confer a fitness advantage to the virus in these human hosts that allows it to rise to proportions detectable by consensus sequencing over the course of a single human infection. We use a mathematical model of within-host virus evolution to estimate the fitness advantage required for a substitution to reach predominance in a single infection as a function of the duration of infection and the fraction of mutant present in the virus population that initially infects a human. The modeling results provide an estimate of the lower bound for the fitness advantage of this adaptive substitution in the currently sequenced A/H7N9 viruses. This framework can be more generally used to quantitatively estimate fitness advantages of adaptive substitutions based on the within-host prevalence of mutations. Such estimates are critical for models of cross-species transmission and host-adaptation of influenza virus infections

Quantifying the selective advantage as a function of substitution prevalence at the start of infection and infection duration.

<p>The minimum selective advantage necessary to reach 50% prevalence in the human host is displayed in color as a function of days of infection (y-axis) and mutant proportion at start of infection (x-axis). Selective advantages of 2.5 and 1 represent the upper and lower bounds of the color bar. The selective advantage exceeds 2.5 for early time points (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076047#pone-0076047-g001" target="_blank">Figure 1A</a>), but for clarity, a threshold was used here. For starting prevalences of >50% no selective advantage is required.</p

Selective advantages when the substitution is absent at the start of infection.

<p>A) The selective advantage required to achieve 50% (black) prevalence of the adaptive substitution within the host after a certain number of days of infection in a situation where the substitution is not present in the infecting virus population (results for 10% and 90% shown in grey). B) The proportion of mutant observed after 3 (dark blue), 6 (blue), 9 (pink), 12 (red) and 15 (dark red) days of infection for a range of selective advantages. The grey bar indicates 50% prevalence.</p

Global spread of dengue virus types: mapping the 70 year history.

Since the first isolation of dengue virus (DENV) in 1943, four types have been identified. Global phenomena such as urbanization and international travel are key factors in facilitating the spread of dengue. Documenting the type-specific record of DENV spread has important implications for understanding patterns in dengue hyperendemicity and disease severity as well as vaccine design and deployment strategies. Existing studies have examined the spread of DENV types at regional or local scales, or described phylogeographic relationships within a single type. Here we summarize the global distribution of confirmed instances of each DENV type from 1943 to 2013 in a series of global maps. These show the worldwide expansion of the types, the expansion of disease hyperendemicity, and the establishment of an increasingly important infectious disease of global public health significance