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J. Exp. Med.,
Volume 187, Number 1, January 5, 1998 25-35
By
From the * Department of Medicine, Division of Hematology-Oncology, 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 inhibit the infectivity of diverse pathogens in vitro, we sought to determine the role of TSP1 in suppression of HIV infectivity. Sequence analysis revealed a TSP1
recognition motif, previously defined for the CD36 gene family of cell adhesion receptors, in
conserved regions flanking the disulfide-linked cysteine residues of the V3 loop of HIV envelope glycoprotein gp120, important for HIV binding to its high affinity cellular receptor CD4.
Using solid-phase in vitro binding assays, we demonstrate direct binding of radiolabeled TSP1
to immobilized recombinant gp120. Based on peptide blocking experiments, the TSP1-gp120
interaction involves CSVTCG sequences in the type 1 properdin-like repeats of TSP1, the
known binding site for CD36. TSP1 and fusion proteins derived from CD36-related TSP1-binding domains were able to compete with radiolabeled soluble CD4 binding to immobilized
gp120. In parallel, purified TSP1 inhibited HIV-1 infection of peripheral blood mononuclear
cells and transformed T and promonocytic cell lines. Levels of TSP1 required for both viral aggregation and direct blockade of HIV-1 infection were physiologic, and affinity depletion of
salivary TSP1 abrogated >70% of the inhibitory effect of whole saliva on HIV infectivity.
Characterization of TSP1-gp120 binding specificity suggests a mechanism for direct blockade
of HIV infectivity that might be exploited to retard HIV transmission that occurs via mucosal
routes.
Laboratory for AIDS Virus
Research, The New York Hospital-Cornell Medical Center, New York 10021
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