Interaction of influenza virus hemagglutinin with target membrane lipids is a key step in virus-induced hemolysis and fusion at pH 5.2.

Abstract

Interaction of influenza virus hemagglutinin with target membrane lipids is a key step in virus-induced hemolysis and fusion at McConnell, March 30, 1981 ABSTRACT The molecular mechanism of hemolysis and fusion by influenza virus in acidic media was studied. First, the effect of trypsin treatment on the activity of fibroblast-grown influenza virus was studied. The results showed that the split form of viral hemagglutinin, HA1 and HA2, but not the precursor, is responsible for the activity. Second, the interaction of egg-grown influenza virus, which contains the split hemagglutinin, with lipid liposomes was studied by spin labeling and electron microscopy. Phospholipid transfer from the viral envelope to the lipid bilayer membrane occurred within 30 s at pH 4.5-5.4. The transfer is largely independent ofthe lipid composition and the crystalline vs. liquid/ crystalline state ofthe membrane. Virus-induced lysis ofliposomes also took place rapidly in the same pH range. Envelope fusion with liposomes occurred at pH 5.2 but not at pH 7.0. These characteristic interactions were similar to those between influenza virus and erythrocytes reported previously. On the other hand, hemagglutinating virus ofJapan did not interact with liposomes at neutral pH. These results suggest that protonation of the NH2-terminal segment of the HA2 form causes interaction of the segment with the lipid core ofthe target cell membrane, leading to hemolysis and fusion.

Haemagglutinin of Influenza A Virus Is a Target for the Antiviral Effect of NorakinR

“…Preliminary experiments using purified virions labelled with 14C-amino acids revealed an effect of Norakin on the attachment of virions to the other membranes of sensitive cells (not shown). It was therefore assumed that Norakin may affect the fusion of the haemagglutinin with the cell membrane, which takes place at acid pH (Maeda et al, 1981;Lenard et al, 1982;Hosaka et al, 1983), and we studied the effect of Norakin on red blood cell lysis induced by FPV at acid pH. These investigations will be described in detail elsewhere.…”

Targeting antibodies to the cytoplasm

“…Hemagglutinin (HA), one of the major surface proteins of human influenza virus, consists of two subunits that promote either cell binding (subunit HA1) or endosomal escape (subunit HA2). 180,181 The HA2 subunit, which promotes endosomal release after undergoing a conformational change at acidic pH, has been employed to enhance PTD mediated delivery. 167,181,182 Transduction of a TAT-Cre fusion protein was enhanced by co-incubation with a chimeric peptide consisting of TAT and the HA2 peptide.…”

Further Studies on the Role of Neuraminidase and the Mechanism of Low pH Dependence in Influenza Virus-induced Membrane Fusion

“…With influenza virus particles, cell fusion and haemolysis are dependent on the presence of both the cleaved haemagglutinin and the neuraminidase (Huang et al, 1981 a). While the requirement for cleaved haemagglutinin has been confirmed by other groups (White et al, 1981 ;Maeda et al, 1981, Lenard & Miller, 1981Lenard et al, 1982), the need for neuraminidase has been disputed. Thus, influenza viruses from which most of the enzyme activity had been destroyed by heat still retained their ability to cause haemolysis (Shibata et al, 1982).…”

“…Another as yet unanswered question concerns the cause of the influenza virus-induced fusion and haemolysis that can be triggered only under slightly acidic conditions (Huang et al, 1981 a;White et al, 1981 ;Maeda et al, 1981 ;Lenard & Miller, 1981). Conformational changes have been reported to occur in the haemagglutinin molecule at pH values optimal for fusion (Skehel et al, 1982;Daniels et al, 1983).…”