IDENTIFICATION OF A CD36-RELATED THROMBOSPONDIN 1-BINDING DOMAIN IN HIV-1 ENVELOPE GLYCOPROTEIN GP120 - RELATIONSHIP TO HIV-1-SPECIFIC INHIBITORY FACTORS IN HUMAN SALIVA

Citation
R. Crombie et al., IDENTIFICATION OF A CD36-RELATED THROMBOSPONDIN 1-BINDING DOMAIN IN HIV-1 ENVELOPE GLYCOPROTEIN GP120 - RELATIONSHIP TO HIV-1-SPECIFIC INHIBITORY FACTORS IN HUMAN SALIVA, The Journal of experimental medicine, 187(1), 1998, pp. 25-35
Citations number
73
Categorie Soggetti
Immunology,"Medicine, Research & Experimental
ISSN journal
00221007
Volume
187
Issue
1
Year of publication
1998
Pages
25 - 35
Database
ISI
SICI code
0022-1007(1998)187:1<25:IOACT1>2.0.ZU;2-R
Abstract
Human and non-human primate salivas retard the infectivity of HIV-1 in vitro and in vivo. Because thrombospondin 1 (TSP1), a high molecular weight trimeric glycoprotein, is concentrated in saliva and can inhibi t the infectivity of diverse pathogens in vitro, we sought to determin e the role of TSP1 in suppression of HIV infectivity. Sequence analysi s revealed a TSP1 recognition motif previously defined for the CD36 ge ne family of cell adhesion receptors, in conserved regions nanking the disulfide-linked cysteine residues of the V3 loop of HIV envelope gly coprotein gp120, important for HIV binding to its high affinity cellul ar receptor CD4. Using solid-phase in vitro binding assays, we demonst rate direct binding of radiolabeled TSP1 to immobilized recombinant gp 120. Based on peptide blocking experiments, the TSP1-gp120 interaction involves CSVTCG sequences in the type 1 properdin-like repeats of TSP 1, the known binding site for CD36. TSP1 and fusion proteins derived f i-om CD36-related TSP1-binding domains were able to compete with radio labeled soluble CD4 binding to immobilized gp120. In parallel, purifie d TSP1 inhibited HIV-1 infection of peripheral blood mononuclear cells and transformed T and promonocytic cell lines. Levels of TSP1 require d for both viral aggregation and direct blockade of HIV-1 infection we re physiologic, and affinity depletion of salivary TSP1 abrogated >70% of the inhibitory effect of whole saliva on HIV infectivity. Characte rization of TSP1-gp120 binding specificity suggests a mechanism for di rect blockade of HIV infectivity that might be exploited to retard HIV transmission that occurs via mucosal routes.