Influenza A viruses continue to be of enormous interest to biomedical researchers and clinicians alike. In addition to the annual influenza epidemics, which have been inferred to cause substantial excess mortality, there is the ever-present threat of a global pandemic due to several features of influenza virus biology. A high mutation rate associated with a segmented negative-sense RNA genome that facilitates recombination confers on these orthomyxoviruses a prodigious ability to evolve in ways that confound and evade the human immune system. The ability of influenza viruses to infect domesticated mammals, such as pigs, as well as birds, both wild and domesticated, provides additional opportunities for the virus to try out new genetic combinations and to disseminate around the globe by means both dependent and independent of human travel.
A recent paper by Jagger et al. (Science 2012) reveals that influenza A viruses are also, not surprisingly, capable of exploiting rather subtle and ingenious genetic “tricks” to maximize the value of every base pair in a total of a mere 13.5 kilobases of genome. These authors have discovered a new influenza gene product, PA-X, that represents a fusion protein incorporating 191 amino-terminal amino acids of the well-known RNA-dependent RNA polymerase (PA) protein and another carboxy-terminal 61 amino acids of a protein from a reading frame shifted by one nucleotide downstream. They present evidence from multiple experiments suggesting that the frameshift is related to a highly conserved codon that is rarely employed in mammalian and avian genomes and therefore interacts with a cognate tRNA of relatively low concentration in the cytosol. The longer-than-average wait for this tRNA to be recruited to the ribosome makes a frameshift mutation more probable. (more…)