Disease relevance of HPIV3gp7

• Six amino-terminal deletion mutants of the NH2-terminally anchored (type II orientation) hemagglutinin-neuraminidase (HN) protein of parainfluenza virus type 3 were expressed in tissue culture by recombinant SV-40 viruses [1].
• When purified dimers of hemagglutinin-neuraminidase molecules released by protease digestion from three strains of human parainfluenza virus 1 were used in crystallization trials, long thin needle crystals formed [2].
• Mice were primed with an HN421-436 peptide that represents the dominant CD4+ T cell epitope on the hemagglutinin-neuraminidase (HN) of Sendai virus [3].
• C28a or wt plaque enlargement, a process that involves cell-cell fusion and does not depend on virion release, is diminished by the presence of 4-GU-DANA, confirming the inhibitory effect of 4-GU-DANA on the fusogenic function of C28a HN [4].
• Expression of the F and HN glycoproteins of human parainfluenza virus type 3 by recombinant vaccinia viruses: contributions of the individual proteins to host immunity [5].

High impact information on HPIV3gp7

• Intracellular processing and transport of NH2-terminally truncated forms of a hemagglutinin-neuraminidase type II glycoprotein [1].
• These latter HN molecules appeared to be folded authentically as assayed by hemagglutination activity, reactivity with a conformation-specific antiserum, correct formation of intramolecular disulfide bonds, and homooligomerization [1].
• HN protein lacking the entire cytoplasmic tail was inserted efficiently into the membrane of the endoplasmic reticulum but was translocated inefficiently into the lumen [1].
• Passive transfer of a CD8(+) T cell supernatant into CD8(+) T cell-depleted, hemagglutinin-neuraminidase (HN)(421-436)-immune muMT mice substantially restored the virus-specific memory CD4(+) response and enhanced viral control in the lung [6].
• F activation was assessed by quantitating the irreversible binding of target erythrocytes (RBC) to HN/F-coexpressing cells in the presence of 4-GU-DANA (zanamivir) to release target cells bound only by HN-receptor interactions; the remaining, irreversibly bound target cells are retained via the fusion protein [7].

Chemical compound and disease context of HPIV3gp7

• Purified H-2Kk and/or partially purified Iak glycoproteins were incorporated into lipid vesicles that contained the hemagglutinin-neuraminidase (HN) glycoprotein and the fusion (F) glycoprotein of Sendai virus [8].
• Relative affinity of the human parainfluenza virus type 3 hemagglutinin-neuraminidase for sialic acid correlates with virus-induced fusion activity [9].
• In the absence of C proteins, there was a significant delay of the incorporation of M protein and both of the envelope proteins, HN and fusion (F) proteins, into progeny virions [10].
• A single amino acid alteration in the human parainfluenza virus type 3 hemagglutinin-neuraminidase glycoprotein confers resistance to the inhibitory effects of zanamivir on receptor binding and neuraminidase activity [11].
• Human parainfluenza virus type 3 HN-receptor interaction: effect of 4-guanidino-Neu5Ac2en on a neuraminidase-deficient variant [4].

Biological context of HPIV3gp7

• We then tested whether mimicking the agglutinating function of the HN molecule with lectins would result in cell fusion [12].
• In order for the fusion protein (F) of HPF3 to promote membrane fusion, the HN must interact with its receptor [9].
• Results of virus recovery from lungs and trachea demonstrated that although immunization with HN or F alone induced an antibody response to the respective glycoproteins, it did not provide a significant level of protection [13].
• C28a but not C28 exhibits a slow fusion phenotype, although determination of the HNs' receptor-binding avidity (with our sensitive method, employing RBC with different degrees of receptor depletion) showed that the receptor-binding avidity of C28a or C28 HN was not lower than that of the wild type [14].
• Cells expressing C28a HN did not bind erythrocytes at 4 degrees C unless pretreated with neuraminidase, but no such pretreatment was required for hemadsorption activity (HAD) at 22 or 37 degrees C. HAD was blocked by 4-GU-DANA, attesting to the ability of this compound to inhibit HN's receptor-binding activity [4].

Anatomical context of HPIV3gp7

• These results provide compelling evidence that the HN molecule of HPF3 and its interaction with neuraminic acid participate in membrane fusion and that cell fusion is mediated by an interaction more complex than mere juxtaposition of the cell membranes [12].
• These findings indicated that the syncytium formation by bovine parainfluenza 3 virus requires both the F and HN proteins and that the extensive syncytium formation by the M virus is due to the M virus HN protein [15].
• We have now examined this mechanism, as well as neuraminidase's role in the viral life cycle, using a neuraminidase-deficient HPF3 variant (C28a) and stable cell lines expressing C28a or wild-type (wt) HN [4].
• Infection of HeLa T4 cells with VF and VHN led to the synthesis of glycoproteins, with the correct apparent molecular weights, that were recognized by monoclonal antibodies specific for HPIV3F and HN [16].
• Finally, we vaccinated colostrum deprived sera-negative calves with the baculo HN recombinant protein and challenged with BPIV-3 [17].

Associations of HPIV3gp7 with chemical compounds

• Increased fusogenicity correlated with single amino acid changes in the HN protein that resulted in increased binding of the variant viruses to the sialic acid receptor [9].
• In the WT infected cells, C proteins appeared to colocalize almost perfectly with the matrix (M) proteins, pretty well with an external envelope glycoprotein (hemagglutinin-neuraminidase [HN]), and very poorly with the internal P protein [10].
• We added a panel of five lectins to the neuraminic acid-deficient cells and showed that binding of these cells to the pi cells did not result in fusion; the lectins could not substitute for interaction of neuraminic acid with the HN molecule in promoting membrane fusion [12].
• We reported previously that 4-guanidino-neu5Ac2en (4-GU-DANA) and related sialic acid-based inhibitors of HPF3 neuraminidase activity also inhibit HN-mediated receptor binding and fusion processes not involving neuraminidase activity [4].
• Surprisingly, analysis of pulse-labeled HN protein by sedimentation on sucrose gradients after labeling periods of as little as 2 min indicated that it was present intracellularly only in oligomeric form [18].

Analytical, diagnostic and therapeutic context of HPIV3gp7

• Here, we demonstrate by immunoelectron microscopy that specific IgA monoclonal antibodies (mAbs) accumulate within Sendai virus-infected polarized cell monolayers and colocalize with the hemagglutinin- neuraminidase (HN) viral protein in a novel intracellular structure [19].
• The results show that mutations in HN conferring altered fusion properties in cell culture also confer striking differences in the ability of HPF3 to cause extensive disease in the cotton rat lung and that this effect is dissociated from any effect on viral replication [20].
• Antigenic and structural properties of the hemagglutinin-neuraminidase glycoprotein of human parainfluenza virus type 3: sequence analysis of variants selected with monoclonal antibodies which inhibit infectivity, hemagglutination, and neuraminidase activities [21].
• Antibody responses in serum were tested by using neutralization and hemagglutination inhibition (HI) assays and a monoclonal antibody blocking immunoassay able to detect antibodies to epitopes within six antigenic sites on the PIV3 hemagglutinin-neuraminidase (HN) glycoprotein and eight antigenic sites on the fusion (F) protein [22].
• A single subcutaneous immunization with these antigen preparations induced a serum antibody response to the HN and F glycoproteins, as determined by plaque neutralization, hemagglutination inhibition, inhibition of virus-induced cell fusion, and immune precipitation tests [23].

References