Table 1 ∣.
Molecular virulence markers and pathogenic determinants of influenza A viruses
| Virulence marker and pathogenic determinant |
Pandemic virus | HPAI virus | Contemporary seasonal virus |
|||||
|---|---|---|---|---|---|---|---|---|
| 1918 H1N1 | 1957 H2N2 | 1968 H3N2 | 2009 H1N1 | H5N1 | H7N7 | H1N1 | H3N2 | |
| HA (binding and fusing with the host cell; antigenic determinant) | ||||||||
| Sialic acid linkage specificity | α-2,6* | α-2,6‡ | α-2,6‡ | α-2,6 and α-2,3§ | α-2,3 | α-2,3∥ | α-2,6 | α-2,6 |
| Residues involved in binding specificity¶ | D190 and D225 | Q226 and N186, or L226 and S228 | L226 and S228 | D190 and D225§; K133# K145#and K222# | G143, T160, N186, Q196, Q226 and G228 | Q226** | D190 and D225 | L226‡‡ and S228 |
| Multibasic cleavage site | No | No | No | No | Yes | Yes | No | No |
| PB1-F2 (induction of apoptosis; promotion of secondary bacterial infection) | ||||||||
| S66 (associated with increased virulence), N66 or truncation | S66 | N66 | N66 | Truncation | S66 or N66§§ | N66 | Truncation | N66 |
| PB2 (temperature-dependent replication competence) | ||||||||
| Adaptation to mammalian hosts | K627 | K627 | K627 | R591 | K627 or N701∥∥ | K627 or N701∥∥ | K627 | K627 |
| NS1 (host antiviral response antagonist) | ||||||||
| PDZ domain-binding motif¶¶ | KSEV | RSKV | RSKV | Truncated | ESEV or EPEV; ~3.3% of H5N1 isolates in 2003 were truncated | ESEV | RSEV | RSKV |
| CPSF30 binding | Yes | Yes## | Yes## | No | Yes## | Yes*** | Yes | Yes |
| E91 associated with virulence | No | No | No | No | Yes‡‡‡ | No | No | No |
| M2 (ion channel) | ||||||||
| Resistant to adamantanes (presence of N31) | No | No | No | Yes | Yes and no§§§ | No | No | Yes |
| NA (receptor-destroying enzyme) | ||||||||
| Resistant to oseltamavir (presence of Y275 and S294) | No | No | No | No∥∥∥ | No∥∥∥ | No | Yes | No |
CPSF30, cleavage and polyadenylation specificity factor 30 kDa subunit; HA, haemagglutinin; HPAI, highly pathogenic avian influenza; NA, neuraminidase; NS1, non-structural protein 1. *Some 1918 virus variants have differential receptor binding, allowing dual α-2,6-linked sialic acid (α-2,6-SA) and α-2,3-SA specificity (see main text for details). ‡Some early human virus isolates contained the α-2,3-SA-binding residues Q226 and Q228. §Residues D190 and D225 are needed for α-2,6-SA binding. Binding to α-2,3-SA is limited; however, the D225G amino acid mutation that is found in a small subset of 2009 pandemic H1N1 isolates from some severe cases confers an increased α-2,3-SA-binding specificity. ∥H7 viruses also show moderate binding to α-2,6-SA owing to a K193 residue. ¶For the HA protein, amino acid positions are according to the H3 numbering. #Part of a positively charged ‘lysine fence’ at the base of the receptor-binding site (identified through structural prediction models) that allows binding to α-2,3-SA and compensates for the lack of the avian E190. **Predicted from amino acid sequence analysis and from a crystal structure of an H7N3 HA in complex with receptor analogues. ‡‡Recent viruses contain either a V (from years 1996–2002) or I (from years 2003–2011) at position 226. §§Natural virus variants can contain either S or N. ∥∥Found in a mouse-adapted H7N7 virus and in some avian H7N7 isolates, and in some avian and human H5N1 isolates. ¶¶Binding to the PDZ domain, a common structural domain of 80–90 amino-acids that is found in the signalling proteins of diverse organisms, has been implicated in virulence: (K/E)(S/P)EV is a strong binding motif, RS(E/K)V displays weak or no binding. ##Some variants have weaker binding. ***Predicted binding; not confirmed experimentally. ‡‡‡Found in viruses that were isolated during the 1997 H5N1 outbreak. §§§Avian and human H5N1 isolates containing the resistant N31 residue or the sensitive S31 residue have been isolated and exist in nature. ∥∥∥ Resistant viruses may occasionally emerge in patients undergoing treatment or prophylaxis.