Tweet
Proc Natl Acad Sci USA. Adaptive strategies of the influenza virus polymerase for replication in humans
Adaptive strategies of the influenza virus polymerase for replication in humans (Proc Natl Acad Sci USA, abstract, edited)
Adaptive strategies of the influenza virus polymerase for replication in humans
1. Andrew Mehle a and 2. Jennifer A. Doudna a,b,c,1
Author Affiliations
1. aDepartments of Molecular and Cell Biology and
2. bChemistry, Howard Hughes Medical Institute, University of California, Berkeley, CA 94705; and
3. cPhysical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
1. Contributed by Jennifer A. Doudna, October 19, 2009 (received for review September 28, 2009)
Abstract
Transmission of influenza viruses into the human population requires surmounting barriers to cross-species infection. Changes in the influenza polymerase overcome one such barrier. Viruses isolated from birds generally contain polymerases with the avian-signature glutamic acid at amino acid 627 in the PB2 subunit. These polymerases display restricted activity in human cells. An adaptive change in this residue from glutamic acid to the human-signature lysine confers high levels of polymerase activity in human cells. This mutation permits escape from a species-specific restriction factor that targets polymerases from avian viruses. A 2009 swine-origin H1N1 influenza A virus recently established a pandemic infection in humans, even though the virus encodes a PB2 with the restrictive glutamic acid at amino acid 627. We show here that the 2009 H1N1 virus has acquired second-site suppressor mutations in its PB2 polymerase subunit that convey enhanced polymerase activity in human cells. Introduction of this polymorphism into the PB2 subunit of a primary avian isolate also increased polymerase activity and viral replication in human and porcine cells. An alternate adaptive strategy has also been identified, whereby introduction of a human PA subunit into an avian polymerase overcomes restriction in human cells. These data reveal a strategy used by the 2009 H1N1 influenza A virus and identify other pathways by which avian and swine-origin viruses may evolve to enhance replication, and potentially pathogenesis, in humans.
* 2009 A(H1N1) * PB2 * species barriers
Footnotes
* 1To whom correspondence should be addressed. E-mail: doudna@berkeley.edu
* Author contributions: A.M. and J.A.D. designed research; A.M. performed research; A.M. contributed new reagents/analytic tools; A.M. and J.A.D. analyzed data; and A.M. and J.A.D. wrote the paper.
* The authors declare no conflict of interest.
* From www.who.int. Accessed September 24, 2009.
* This article contains supporting information online at https://www.pnas.org/cgi/content/ful...DCSupplemental.
-
<cite cite="http://www.pnas.org/content/106/50/21312.short?rss=1">Adaptive strategies of the influenza virus polymerase for replication in humans ? PNAS</cite>
1. Andrew Mehle a and 2. Jennifer A. Doudna a,b,c,1
Author Affiliations
1. aDepartments of Molecular and Cell Biology and
2. bChemistry, Howard Hughes Medical Institute, University of California, Berkeley, CA 94705; and
3. cPhysical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
1. Contributed by Jennifer A. Doudna, October 19, 2009 (received for review September 28, 2009)
Abstract
Transmission of influenza viruses into the human population requires surmounting barriers to cross-species infection. Changes in the influenza polymerase overcome one such barrier. Viruses isolated from birds generally contain polymerases with the avian-signature glutamic acid at amino acid 627 in the PB2 subunit. These polymerases display restricted activity in human cells. An adaptive change in this residue from glutamic acid to the human-signature lysine confers high levels of polymerase activity in human cells. This mutation permits escape from a species-specific restriction factor that targets polymerases from avian viruses. A 2009 swine-origin H1N1 influenza A virus recently established a pandemic infection in humans, even though the virus encodes a PB2 with the restrictive glutamic acid at amino acid 627. We show here that the 2009 H1N1 virus has acquired second-site suppressor mutations in its PB2 polymerase subunit that convey enhanced polymerase activity in human cells. Introduction of this polymorphism into the PB2 subunit of a primary avian isolate also increased polymerase activity and viral replication in human and porcine cells. An alternate adaptive strategy has also been identified, whereby introduction of a human PA subunit into an avian polymerase overcomes restriction in human cells. These data reveal a strategy used by the 2009 H1N1 influenza A virus and identify other pathways by which avian and swine-origin viruses may evolve to enhance replication, and potentially pathogenesis, in humans.
* 2009 A(H1N1) * PB2 * species barriers
Footnotes
* 1To whom correspondence should be addressed. E-mail: doudna@berkeley.edu
* Author contributions: A.M. and J.A.D. designed research; A.M. performed research; A.M. contributed new reagents/analytic tools; A.M. and J.A.D. analyzed data; and A.M. and J.A.D. wrote the paper.
* The authors declare no conflict of interest.
* From www.who.int. Accessed September 24, 2009.
* This article contains supporting information online at https://www.pnas.org/cgi/content/ful...DCSupplemental.
-