TABLE 1 | Molecular virulence markers and pathogenic determinants of influenza A viruses

From the following article:

Influenza A viruses: new research developments

Rafael A. Medina & Adolfo García-Sastre

Nature Reviews Microbiology 9, 590-603 (August 2011)


Virulence marker and pathogenic determinantPandemic virusHPAI virusContemporary seasonal virus
 1918 H1N11957 H2N21968 H3N22009 H1N1H5N1H7N7H1N1H3N2
HA (binding and fusing with the host cell; antigenic determinant)
Sialic acid linkage specificityα-2,6*α-2,6α-2,6α-2,6 and α-2,3§α-2,3α-2,3||α-2,6α-2,6
Residues involved in binding specificityD190 and D225Q226 and N186, orL226 and S228L226 and S228D190 and D225§;K133#, K145# and K222#G143, T160, N186, Q196, Q226 and G228Q226**D190 and D225L226 and S228
Multibasic cleavage siteNoNoNoNoYesYesNoNo
PB1–F2 (induction of apoptosis; promotion of secondary bacterial infection)
S66 (associated with increased virulence), N66 or truncationS66N66N66TruncationS66 or N66N66TruncationN66
PB2 (temperature-dependent replication competence)
Adaptation to mammalian hostsK627K627K627R591K627 or N701||||K627 or N701||||K627K627
NS1 (host antiviral response antagonist)
PDZ domain-binding motif¶¶KSEVRSKVRSKVTruncatedESEV or EPEV; ~3.3% of H5N1 isolates in 2003 were truncatedESEVRSEVRSKV
CPSF30 bindingYesYes##Yes##NoYes##Yes***YesYes
E91 associated with virulenceNoNoNoNoYesNoNoNo
M2 (ion channel)
Resistant to adamantanes (presence of N31)NoNoNoYesYes and no§§§NoNoYes
NA (receptor-destroying enzyme)
Resistant to oseltamavir (presence of Y275 and S294)NoNoNoNo||||||No||||||NoYesNo
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.

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