Abstract
Heparan sulfate proteoglycans (HSPG) can act as binding receptors for certain laboratory-adapted (TCA) strains of feline immunodeficiency virus (FIV) and human immunodeficiency virus (HIV). Heparin, a soluble heparin sulfate (HS), can inhibit TCA HIV and FIV entry mediated by HSPG interaction in vitro. In the present study, we further determined the selective interaction of heparin with the V3 loop of TCA of FIV. Our current results indicate that heparin selectively inhibits infection by TCA strains, but not for field isolates (FS). Heparin also specifically interferes with TCA surface glycoprotein (SU) binding to CXCR4, by interactions with HSPG binding sites on the V3 loop of the FIV envelope protein. Peptides representing either the N- or C-terminal side of the V3 loop and containing HSPG binding sites were able to compete away the heparin block of TCA SU binding to CXCR4. Heparin does not interfere with the interaction of SU with anti-V3 antibodies that target the CXCR4 binding region or with the interaction between FS FIV and anti-V3 antibodies since FS SU has no HSPG binding sites within the HSPG binding region. Our data show that heparin blocks TCA FIV infection or entry not only through its competition of HSPG on the cell surface interaction with SU, but also by its interference with CXCR4 binding to SU. These studies aid in the design and development of heparin derivatives or analogues that can inhibit steps in virus infection and are informative regarding the HSPG/SU interaction.
Highlights
The inhibition ratios of heparin interference of CXCR4 binding for most mutants was less than 30%, which was similar to the situation with PPR (p.0.05) but not PPRcr (p,0.01)
The inhibition ratio of Q396N by heparin was greater than 50%, it was still less than that observed for the effect of heparin on 34TF10 (TCA) surface glycoprotein (SU) (p,0.05)
Our data indicated that the CXCR4 binding region was not directly involved in heparin/SU interactions; the extent to which heparin interfered with CXCR4 binding may be influenced by the position or the type of amino acid residue in the N44 region
Summary
Heparan sulfate proteoglycans (HSPG) are a type of glycosaminoglycans (GAG) that participate in a number of biological processes as diverse as cell adhesion and migration [1,2,3], cell growth and proliferation [4, 5], inflammation [2, 6], angiogenesis [7, 8], tumor metastasis [5, 9, 10], or cellular attachment of many viruses [11,12,13,14], including retrovirus family members such as HIV and FIV [15,16,17,18]. As highly sulfated heparin-like IdoA-(1R4)GlcNS disaccharide (NS) domains are the functionally significant parts of HS in HS–protein binding [20, 21], more abundant heparin and heparin-derived oligosaccharides have been used as models for HS. Because heparin has therapy potential for function as a tumor metastasis modulator [27, 29], antiviral interference [30,31,32,33,34], and serves as a model for the interaction of proteins with cell-surface HSPG [21] described above, it is of great significance to further study and understand heparin/protein interaction
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