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A single site for N-linked glycosylation in the envelope glycoprotein of feline immunodeficiency virus modulates the virus-receptor interaction.

Willett BJ, McMonagle EL, Logan N, Samman A, Hosie MJ - Retrovirology (2008)

Bottom Line: Prototypic FIV vaccines based on the FL4 strain of FIV contain a cell culture-adapted strain of FIV Petaluma, a CD134-independent strain of FIV that interacts directly with CXCR4.In addition to a characteristic increase in charge in the V3 loop homologue of FIVFL4, we identified two mutations in potential sites for N-linked glycosylation in the region of FIV Env analogous to the V1-V2 region of HIV and SIV Env, T271I and N342Y.The T271I mutation did not confer CD134-independent infection upon GL8 or CPG41, nor did it increase the affinity of the CXCR4 interaction, suggesting that the principal effect was targeted at reducing the complexity of the Env-CD134 interaction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Retrovirus Research Laboratory, Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow, G61 1QH, UK. b.willett@vet.gla.ac.uk

ABSTRACT
Feline immunodeficiency virus (FIV) targets helper T cells by attachment of the envelope glycoprotein (Env) to CD134, a subsequent interaction with CXCR4 then facilitating the process of viral entry. As the CXCR4 binding site is not exposed until CD134-binding has occurred then the virus is protected from neutralising antibodies targeting the CXCR4-binding site on Env. Prototypic FIV vaccines based on the FL4 strain of FIV contain a cell culture-adapted strain of FIV Petaluma, a CD134-independent strain of FIV that interacts directly with CXCR4. In addition to a characteristic increase in charge in the V3 loop homologue of FIVFL4, we identified two mutations in potential sites for N-linked glycosylation in the region of FIV Env analogous to the V1-V2 region of HIV and SIV Env, T271I and N342Y. When these mutations were introduced into the primary GL8 and CPG41 strains of FIV, the T271I mutation was found to alter the nature of the virus-CD134 interaction; primary viruses carrying the T271I mutation no longer required determinants in cysteine-rich domain (CRD) 2 of CD134 for viral entry. The T271I mutation did not confer CD134-independent infection upon GL8 or CPG41, nor did it increase the affinity of the CXCR4 interaction, suggesting that the principal effect was targeted at reducing the complexity of the Env-CD134 interaction.

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A. Schematic structural model of the FIV SU proteins illustrating the locations of the T271I and N342Y mutations (red), conserved cysteine residues (green) and predicted sites for N-linked glycosylation (). Residues in the V1/V2 or V3 homologues displaying >10% variation from the consensus sequence are shaded. B. Position-specific scoring matrix (PSSM) analysis of amino acids 248 to 445 of FIV SU encompassing the homologous regions to HIV V1/V2 and V3 illustrating the likelihood of the consensus amino acid appearing in an SU sequence. T271 and N342 are arrowed.
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Figure 1: A. Schematic structural model of the FIV SU proteins illustrating the locations of the T271I and N342Y mutations (red), conserved cysteine residues (green) and predicted sites for N-linked glycosylation (). Residues in the V1/V2 or V3 homologues displaying >10% variation from the consensus sequence are shaded. B. Position-specific scoring matrix (PSSM) analysis of amino acids 248 to 445 of FIV SU encompassing the homologous regions to HIV V1/V2 and V3 illustrating the likelihood of the consensus amino acid appearing in an SU sequence. T271 and N342 are arrowed.

Mentions: We next examined the predicted locations of T271I and N342Y substitutions on the FIV SU protein, comparing the locations with schematic structural models for FIV SU and HIV SU based on predictive algorithms for secondary structure [74], disulphide bond architecture [75,75,76] and informed by the solved crystal structure of HIV Env [7,8]. T271I and N342Y are predicted to lie in a region of FIV SU which may be analogous to the area at the base of the HIV V1 and V2 stem (Fig. 1A). For the purpose of this study, and to assist with direct comparisons between FIV and HIV, this region is referred to as the V1/V2 homologue herein. Although this region of FIV Env was thought formerly to be relatively conserved, a reappraisal based on accumulated Env sequence data indicates pockets of variability within this region, as illustrated when variability is plotted using consensus position-specific scoring matrix analysis [77] (PSSM, Fig. 1B). Mutations in the V1/V2 region of HIV SU affect the interaction between the HIV SU and its receptor and co-receptor(s) and alter the antigenicity of the envelope glycoprotein, promoting the production of antibodies targeting the CD4 binding site [12,73,78,79]. Similarly, for HIV loss of N-linked glycans from this region contribute to CD4-independence [12].


A single site for N-linked glycosylation in the envelope glycoprotein of feline immunodeficiency virus modulates the virus-receptor interaction.

Willett BJ, McMonagle EL, Logan N, Samman A, Hosie MJ - Retrovirology (2008)

A. Schematic structural model of the FIV SU proteins illustrating the locations of the T271I and N342Y mutations (red), conserved cysteine residues (green) and predicted sites for N-linked glycosylation (). Residues in the V1/V2 or V3 homologues displaying >10% variation from the consensus sequence are shaded. B. Position-specific scoring matrix (PSSM) analysis of amino acids 248 to 445 of FIV SU encompassing the homologous regions to HIV V1/V2 and V3 illustrating the likelihood of the consensus amino acid appearing in an SU sequence. T271 and N342 are arrowed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2563026&req=5

Figure 1: A. Schematic structural model of the FIV SU proteins illustrating the locations of the T271I and N342Y mutations (red), conserved cysteine residues (green) and predicted sites for N-linked glycosylation (). Residues in the V1/V2 or V3 homologues displaying >10% variation from the consensus sequence are shaded. B. Position-specific scoring matrix (PSSM) analysis of amino acids 248 to 445 of FIV SU encompassing the homologous regions to HIV V1/V2 and V3 illustrating the likelihood of the consensus amino acid appearing in an SU sequence. T271 and N342 are arrowed.
Mentions: We next examined the predicted locations of T271I and N342Y substitutions on the FIV SU protein, comparing the locations with schematic structural models for FIV SU and HIV SU based on predictive algorithms for secondary structure [74], disulphide bond architecture [75,75,76] and informed by the solved crystal structure of HIV Env [7,8]. T271I and N342Y are predicted to lie in a region of FIV SU which may be analogous to the area at the base of the HIV V1 and V2 stem (Fig. 1A). For the purpose of this study, and to assist with direct comparisons between FIV and HIV, this region is referred to as the V1/V2 homologue herein. Although this region of FIV Env was thought formerly to be relatively conserved, a reappraisal based on accumulated Env sequence data indicates pockets of variability within this region, as illustrated when variability is plotted using consensus position-specific scoring matrix analysis [77] (PSSM, Fig. 1B). Mutations in the V1/V2 region of HIV SU affect the interaction between the HIV SU and its receptor and co-receptor(s) and alter the antigenicity of the envelope glycoprotein, promoting the production of antibodies targeting the CD4 binding site [12,73,78,79]. Similarly, for HIV loss of N-linked glycans from this region contribute to CD4-independence [12].

Bottom Line: Prototypic FIV vaccines based on the FL4 strain of FIV contain a cell culture-adapted strain of FIV Petaluma, a CD134-independent strain of FIV that interacts directly with CXCR4.In addition to a characteristic increase in charge in the V3 loop homologue of FIVFL4, we identified two mutations in potential sites for N-linked glycosylation in the region of FIV Env analogous to the V1-V2 region of HIV and SIV Env, T271I and N342Y.The T271I mutation did not confer CD134-independent infection upon GL8 or CPG41, nor did it increase the affinity of the CXCR4 interaction, suggesting that the principal effect was targeted at reducing the complexity of the Env-CD134 interaction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Retrovirus Research Laboratory, Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow, G61 1QH, UK. b.willett@vet.gla.ac.uk

ABSTRACT
Feline immunodeficiency virus (FIV) targets helper T cells by attachment of the envelope glycoprotein (Env) to CD134, a subsequent interaction with CXCR4 then facilitating the process of viral entry. As the CXCR4 binding site is not exposed until CD134-binding has occurred then the virus is protected from neutralising antibodies targeting the CXCR4-binding site on Env. Prototypic FIV vaccines based on the FL4 strain of FIV contain a cell culture-adapted strain of FIV Petaluma, a CD134-independent strain of FIV that interacts directly with CXCR4. In addition to a characteristic increase in charge in the V3 loop homologue of FIVFL4, we identified two mutations in potential sites for N-linked glycosylation in the region of FIV Env analogous to the V1-V2 region of HIV and SIV Env, T271I and N342Y. When these mutations were introduced into the primary GL8 and CPG41 strains of FIV, the T271I mutation was found to alter the nature of the virus-CD134 interaction; primary viruses carrying the T271I mutation no longer required determinants in cysteine-rich domain (CRD) 2 of CD134 for viral entry. The T271I mutation did not confer CD134-independent infection upon GL8 or CPG41, nor did it increase the affinity of the CXCR4 interaction, suggesting that the principal effect was targeted at reducing the complexity of the Env-CD134 interaction.

Show MeSH
Related in: MedlinePlus