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Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with alpha2-3-linked sialic acids that are distinct from those bound by H5 avian influenza virus hemagglutinin.

ABSTRACT: We investigated the binding of human parainfluenza virus types 1 and 3 (hPIV1 and hPIV3, respectively) to the glycan array of the Consortium for Functional Glycomics and binding and their release from erythrocytes under conditions where neuraminidase is inactive or active. hPIV1 and hPIV3 bind modifications of Neu5Acalpha2-3Galbeta1-4GlcNAc, including the sialyl-Lewis(x) motif and structures containing 6-sulfogalactose. hPIV1 and hPIV3 thus bind typical N-linked glycans, in contrast to avian influenza virus H5 hemagglutinin (J. Stevens, O. Blixt, T. M. Tumpey, J. K. Taubenberger, J. C. Paulson, and I. A. Wilson, Science 312:404-410, 2006), which binds less-common motifs. While the receptor is not the sole determinant of tropism, hPIV or H5 influenza virus infection of specific cells that express receptors may contribute to their different pathologies.

SUBMITTER: Amonsen M

PROVIDER: S-EPMC1951310 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with alpha2-3-linked sialic acids that are distinct from those bound by H5 avian influenza virus hemagglutinin.

Amonsen Mary M Smith David F DF Cummings Richard D RD Air Gillian M GM

Journal of virology 20070523 15

We investigated the binding of human parainfluenza virus types 1 and 3 (hPIV1 and hPIV3, respectively) to the glycan array of the Consortium for Functional Glycomics and binding and their release from erythrocytes under conditions where neuraminidase is inactive or active. hPIV1 and hPIV3 bind modifications of Neu5Acalpha2-3Galbeta1-4GlcNAc, including the sialyl-Lewis(x) motif and structures containing 6-sulfogalactose. hPIV1 and hPIV3 thus bind typical N-linked glycans, in contrast to avian inf ...[more]

PMID: 17522226

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Project description:Live attenuated recombinant human parainfluenza virus type 1 (rHPIV1) was investigated as a vector to express the respiratory syncytial virus (RSV) fusion (F) glycoprotein, to provide a bivalent vaccine against RSV and HPIV1. The RSV F gene was engineered to include HPIV1 transcription signals and inserted individually into three gene locations in each of the two attenuated rHPIV1 backbones. Each backbone contained a single previously described attenuating mutation that was stabilized against deattenuation, specifically, a non-temperature-sensitive deletion mutation involving 6 nucleotides in the overlapping P/C open reading frames (ORFs) (C(?170)) or a temperature-sensitive missense mutation in the L ORF (L(Y942A)). The insertion sites in the genome were pre-N (F1), N-P (F2), or P-M (F3) and were identical for both backbones. In vitro, the presence of the F insert reduced the rate of virus replication, but the final titers were the same as the final titer of wild-type (wt) HPIV1. High levels of RSV F expression in cultured cells were observed with rHPIV1-C(?170)-F1, -F2, and -F3 and rHPIV1-L(Y942A)-F1. In hamsters, the rHPIV1-C(?170)-F1, -F2, and -F3 vectors were moderately restricted in the nasal turbinates, highly restricted in lungs, and genetically stable in vivo. Among the C(?170) vectors, the F1 virus was the most immunogenic and protective against wt RSV challenge. The rHPIV1-L(Y942A) vectors were highly restricted in vivo and were not detectably immunogenic or protective, indicative of overattenuation. The C(?170)-F1 construct appears to be suitably attenuated and immunogenic for further development as a bivalent intranasal pediatric vaccine.There are no vaccines for the pediatric respiratory pathogens RSV and HPIV. We are developing live attenuated RSV and HPIV vaccines for use in virus-naive infants. Live attenuated RSV strains in particular are difficult to develop due to their poor growth and physical instability, but these obstacles could be avoided by the use of a vaccine vector. We describe the development and preclinical evaluation of live attenuated rHPIV1 vectors expressing the RSV F protein. Two different attenuated rHPIV1 backbones were each engineered to express RSV F from three different gene positions. The rHPIV1-C(?170)-F1 vector, bearing an attenuating deletion mutation (C(?170)) in the P/C gene and expressing RSV F from the pre-N position, was attenuated, stable, and immunogenic against the RSV F protein and HPIV1 in the hamster model and provided substantial protection against RSV challenge. This study provides a candidate rHPIV1-RSV-F vaccine virus suitable for continued development as a bivalent vaccine against two major childhood pathogens.

Project description:UnlabelledHighly pathogenic avian influenza viruses of the H5N1 subtype continue to circulate in poultry in Asia, Africa, and the Middle East. Recently, outbreaks of novel reassortant H5 viruses have also occurred in North America. Although the number of human infections with highly pathogenic H5N1 influenza viruses continues to rise, these viruses remain unable to efficiently transmit between humans. However, we and others have identified H5 viruses capable of respiratory droplet transmission in ferrets. Two experimentally introduced mutations in the viral hemagglutinin (HA) receptor-binding domain conferred binding to human-type receptors but reduced HA stability. Compensatory mutations in HA (acquired during virus replication in ferrets) were essential to restore HA stability. These stabilizing mutations in HA also affected the pH at which HA undergoes an irreversible switch to its fusogenic form in host endosomes, a crucial step for virus infectivity. To identify additional stabilizing mutations in an H5 HA, we subjected a virus library possessing random mutations in the ectodomain of an H5 HA (altered to bind human-type receptors) to three rounds of treatment at 50°C. We isolated several mutants that maintained their human-type receptor-binding preference but acquired an appreciable increase in heat stability and underwent membrane fusion at a lower pH; collectively, these properties may aid H5 virus respiratory droplet transmission in mammals.ImportanceWe have identified mutations in HA that increase its heat stability and affect the pH that triggers an irreversible conformational change (a prerequisite for virus infectivity). These mutations were identified in the genetic background of an H5 HA protein that was mutated to bind to human cells. The ability to bind to human-type receptors, together with physical stability and an altered pH threshold for HA conformational change, may facilitate avian influenza virus transmission via respiratory droplets in mammals.

Dataset Information

Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with alpha2-3-linked sialic acids that are distinct from those bound by H5 avian influenza virus hemagglutinin.

Publications

Human parainfluenza viruses hPIV1 and hPIV3 bind oligosaccharides with alpha2-3-linked sialic acids that are distinct from those bound by H5 avian influenza virus hemagglutinin.

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