Page 13 - Avian Virology: Current Research and Future Trends

6 | Perez et al.

of influenza A virus needs to be further clarified (Li et al., replication and, thus, it is one of the features that contributes
2014a). IFN-sensitive mutations have been identified in several to the rapid evolutionary rate of these viruses. PB1 interacts
of the viral protein products, including PB2 suggesting that the directly with PA through the first 11 N-terminal amino acids
virus carries several strategies to counteract the host’s antiviral (Pérez and Donis, 1995, 2001; González et al., 1996) and with
response (Du et al., 2018). PB2’s role as a host restriction PB2 through a C-terminal domain spanning amino acids 685
factor is well described, particularly mutations that occur at through 757 (González et al., 1996; Poole et al., 2007; Sugiy-
amino acids 627 and 701 (Gorman et al., 1990; Subbarao ama et al., 2009). PB1 contains a bi-partite NLS signal between
et al., 1993; Resa-Infante et al., 2008; Le et al., 2009; Resa- amino acids 187–190 and 207–211, which is recognized by
Infante et al., 2011; Gabriel et al., 2013). At amino acid 627 the host’s alpha importin RanBP5 nuclear transport protein
the mutation from glutamic acid to lysine (E627K) improves (Akkina et al., 1987.; Hutchinson et al., 2011).
respiratory tropism and virulence in mammals (Subbarao et al., PB1-N40 is a truncated form of PB1 that lacks polymerase
1993; Crescenzo-Chaigne et al., 2002; Aggarwal et al., 2011; activity. PB1-N40 initiates from an alternative translation ini-
Bogs et al., 2011; Ng et al., 2012; Tian et al., 2012; Wang et tiation site located 115 nucleotides downstream of the canonical
al., 2012; de Jong et al., 2013; Cheng et al., 2014; Danzy et PB1 initiation site (Wise et al., 2009). PB1-N40 lacks the PA
al., 2014; Jonges et al., 2014; Paterson et al., 2014; H. Zhang binding domain but retains the PB2 binding domain. The role
et al., 2014; Weber et al., 2015). Glutamic acid 627 is highly of PB1-N40 has not been fully elucidated, its expression is not
conserved among IAVs of avian origin. In contrast, Lysine essential for virus replication. A balanced, interdependent effect is
627 is found in most IAVs adapted to humans. Recent studies observed between the expression of PB1, PB1-N40 and PB1-F2:
suggest that amino acid 627, which overlaps the NP bind- The loss of PB1-N40 expression in the presence of an intact
ing site, along with amino acid changes in NP, modulate the PB1-F2 gene leads to a replication defect in vitro in tissue culture
interaction between these two proteins and impact the virus’ cells (Wise et al., 2009).
ability to replicate and cause disease in mammals. The amino PB1-F2 is encoded by an alternative +1 ORF with respect to
acid changes aspartic acid 701 to asparagine (D701N) near the PB1 gene (Chen et al., 2001; Gibbs et al., 2003b). The two
the NLS-1 site favours binding to human importin alpha-1 most common forms of PB1-F2 are of 90 and 57 amino acids
and decreases binding to the avian counterpart (Gabriel et al., in length although minor populations are observed that include
2008). Other amino acid mutations have been described to lengths of 52, 63, 79, 81, 87, and 101 amino acids (reviewed
impact host range, although they may do so in a strain specific in Krumbholz et al., 2011; Košík et al., 2013). By localizing
manner (Gabriel et al., 2005, 2013; Herfst et al., 2010; Yamada to the inner mitochondrial membrane in IAV-infected cells
et al., 2010; Mok et al., 2011, 2014). (Chanturiya et al., 2004), PB1-F2 appears to enhance virus-
More recently, a second gene product was discovered from induced cell death in a cell type-dependent manner and it can
segment 2: PB2-S1, is produced from a spliced mRNA in which promote inflammation; the C-terminal region spanning amino
the region corresponding to nucleotides 1513 to 1894 of the acids 58 through 87 is important for such activities (Chan-
PB2 mRNA is deleted (Yamayoshi et al., 2016). PB2-S1 was turiya et al., 2004; Yamada et al., 2004; Zamarin et al., 2005;
detected in virus-infected canine-origin cells (but not in avian Conenello and Palese, 2007; Conenello et al., 2007; Kamal et
cells), localized to mitochondria, inhibited the RIG-I-dependent al., 2017). PB1-F2 interacts with the inner mitochondrial mem-
interferon signalling pathway, and interfered with viral polymer- brane adenine nucleotide translocator 3 (ANT3) and the outer
ase activity (dependent on its PB1-binding capability). PB2-S1, mitochondrial membrane voltage-dependent anion channel
however, is not essential for virus replication in vitro and its 1 (VDAC1), both of which are implicated in the mitochon-
in vivo significance requires further studies (Yamayoshi et al., drial permeability transition during apoptosis (Zamarin et al.,
2016). 2005). The N-terminal end of PB1-F2, within amino acids 1
through 50, can interact with PB1 resulting in up-regulation of
Segment 2: PB1, PB1-N40 and PB1-F2 polymerase activity (Mazur et al., 2008; Košík et al., 2011). Of
Segment 2 encodes the polymerase subunit PB1, the note, the 2009 pandemic H1N1 strain carries a PB1-F2 ORF
N-terminally truncated PB1-N40 and the small PB1-F2 pro- of just 11 amino acids, suggesting that its significance for virus
tein. The PB1 subunit contains overlapping binding domains replication is likely strain-and host cell-dependent (Pena et al.,
for vRNA, PA, and PB2. PB1 has conserved motifs character- 2012b). PB1-F2 inhibits IFN production by binding to MAVS
istic of RNA-dependent RNA polymerases (Kobayashi et al., and decreasing mitochondrial membrane potential (Varga et al.,
1996a; Toyoda et al., 1996) and binds the vRNA panhandle 2011, 2012). PB1-F2 is highly conserved among IAVs of avian
through domains located within the first N-terminal 83 amino origin (Schmolke et al., 2011). Removal of the PB1-F2 ORF in
acids and a C-terminal region downstream of amino acid 483 a prototypical HPAIV H5N1 delayed the onset of clinical signs
(González and Ortín, 1999; Kolpashchikov et al., 2004; Jung and systemic spread of the virus in mallard ducks (Schmolke et
and Brownlee, 2006; Binh et al., 2014). The N-terminal region al., 2011). An amino acid mutation from asparagine to serine at
participates also in binding the replication intermediate posi- position 66 in PB1-F2 appears to modulate virulence and pro-
tive sense complementary RNA (cRNA) along with a region mote secondary bacterial infection, but such effects are strain
between positions 267 and 493. PB1 lacks proof reading activity and host specific (McAuley et al., 2007, 2010, 2013; Pena et al.,
which leads to approximately one mutation per genome during 2012a; Schmolke et al., 2011). Alternative amino acid mutations