270 Syndecans on the Vascular Endothelium Serve as a Major in trans Viral Reservoir for HIV M. Bobardt, A. Saphire, P. Gallay* Scripps Res Inst, La Jolla, CA
Background: We obtained several lines of evidence which suggest that a class of cell surface transmembrane proteoglycans-the syndecans-serve as in trans receptors for HIV. Specifically, syndecans by capturing HIV via their heparan sulfate chains promote HIV attachment to nonpermissive CD4-negative cells. Although they enhance HIV adsorption, syndecans do not substitute for CD4 and chemokine entry receptors. However, HIV attached to syndecans on nonpermissive cells serves as a source of in trans infectivity for permissive CD4-positive cells. We found that syndecans act as in trans receptors for a broad range of lentiviruses including primary viruses produced from physiological PBMCs. This latter observation is critical, because it demonstrates that HIV-syndecan interactions may also occur in vivo.
Method: Recently, we found that gp120 is the ligand for syndecans when the virus originates from PBMCs in contrast to 293T-derived virus. Previous work using recombinant gp120 suggested that the number of basic residues within gp120 V3 loop governs HIV recognition of heparans. However, our most recent work using a large panel of primary viruses shows that viruses containing only few basic residues within the V3 loop may attach more efficiently to syndecans than viruses containing many basic residues.
Results: This suggests that neither the number of basic residues in the V3 loop nor the tropism dictates the interaction of HIV with syndecans, and that the gp120 domains necessary for HIV binding to heparans remain to be identified. Importantly, we found that syndecans preserve virus infectivity for a week, whereas unbound virus loses its infectivity in less than a day. Moreover, we obtained evidence linking syndecans to HIV pathogenesis. Specifically, we showed that endothelial cells in vivo richly express syndecans and possess a remarkable capacity to attach and transfer HIV to T-cells. Most importantly, this mode of transmission promotes the efficiency of HIV propagation to T-cells. Thus, our data not only indicate that HIV bound to syndecans on the endothelium is retained in an infectious state for several days and can be transmitted to circulating T-cells, but that endothelial syndecans boost HIV replication in T-cells in trans.
Conclusions: Thus, the endothelium represents an abundant in trans viral reservoir for T-cells. We can envision that in the capillaries where the velocity of the blood flow is tranquil, this mode of transmission provided by syndecans represents hot spots for HIV replication.
