Serological evidence of human infections with highly pathogenic avian influenza A(H5N1) virus: a systematic review and meta-analysis

Abstract

Background Highly pathogenic avian influenza A(H5N1) virus poses a global public health threat given severe and fatal zoonotic infections since 1997 and ongoing A(H5N1) virus circulation among poultry in several countries. A comprehensive assessment of the seroprevalence of A(H5N1) virus antibodies remains a gap and limits understanding of the true risk of A(H5N1) virus infection. Methods We conducted a systematic review and meta-analysis of published serosurveys to assess the risk of subclinical and clinically mild A(H5N1) virus infections. We assessed A(H5N1) virus antibody titers and changes in titers among populations with variable exposures to different A(H5N1) viruses. Results Across studies using the World Health Organization-recommended seropositive definition, the point estimates of the seroprevalence of A(H5N1) virus-specific antibodies were higher in poultry-exposed populations (range 0–0.6%) and persons exposed to both human A(H5N1) cases and infected birds (range 0.4–1.8%) than in close contacts of A(H5N1) cases or the general population (none to very low frequencies). Seroprevalence was higher in persons exposed to A(H5N1) clade 0 virus (1.9%, range 0.7–3.2%) than in participants exposed to other clades of A(H5N1) virus (range 0–0.5%) (p < 0.05). Seroprevalence was higher in poultry-exposed populations (range 0–1.9%) if such studies utilized antigenically similar A(H5N1) virus antigens in assays to A(H5N1) viruses circulating among poultry. Conclusions These low seroprevalences suggest that subclinical and clinically mild human A(H5N1) virus infections are uncommon. Standardized serological survey and laboratory methods are needed to fully understand the extent and risk of human A(H5N1) virus infections.

Amino Acid Residues Involved in Inhibition of Host Gene Expression by Influenza A/Brevig Mission/1/1918 PA-X

“…Amino acid changes affecting 1918 PA-X's shutoff activity also affected the ability of 1918 PA-X to inhibit IFN responses after SeV infection measured by the expression levels of Fluc driven by an ISRE element (Figure 7A), as previously shown for other IAV PA-X mutants [34]. These data is consistent with previous data showing that the PA-X protein efficiently counteracts IFN responses [14,17,21,36]. Given that IFN responses include the induction of genes with antiviral activity, controlling viral replication [37], and that PA-X modulates virus pathogenesis [19], it is very likely that the identified mutations in PA-X affect virus fitness and pathogenesis.…”

Amino acid residues involved in inhibition of host gene expression by influenza A/Brevig Mission/1/1918 PA-X

“…However, activation of ISRE promoter in cells transfected with 1918 PA-X proteins was significantly reduced (Figure 7A). These data is consistent with previous data showing that PA-X protein efficiently counteracts IFN responses [13,16,33,38]. Interestingly, 1918 PA-X mutants inhibiting ISRE promoter activation to higher extend (L109R, T123A, R168G, T98I/P103S and H146Y/L187P) were the ones showing higher shutoff activity.…”

Natural Selection of H5N1 Avian Influenza A Viruses with Increased PA-X and NS1 Shutoff Activity

“…The amino acid change L221R was selected later, with most of the H5N1 IAV isolates from 2001 to 2005 encoding the residue circulating nowadays ( Table 1 ). Notably, H5N1 IAV containing the residues most common in avian isolates were also the ones most frequently infecting humans ( Table 2 ), as could be expected taking into account that most of the infections in humans occur in subjects in close contact with infected avian species [ 47 ]. In H5N1 IAV isolated from humans, PA-X residues T20, A85, T118, G209, V212, L221, and Q250 were present in viruses infecting humans during 1996–1997.…”