Syndecans Serve as Attachment Receptors for Human Immunodeficiency Virus Type 1 on Macrophages

Autor: Zhe Zhang, Andrew C. S. Saphire, Michael Bobardt, Philippe Gallay, Guido David
Rok vydání: 2001
Předmět:
Zdroj: Journal of Virology. 75:9187-9200
ISSN: 1098-5514
0022-538X
DOI: 10.1128/jvi.75.19.9187-9200.2001
Popis: To date, the human immunodeficiency virus type 1 (HIV-1) receptor complex known to be essential for virus entry consists of CD4 molecules expressed on T cells, macrophages, dendritic cells, and microglia and a member of the seven-transmembrane chemokine receptor family. It is thought that HIV-1 initiates its attachment to host cells via an interaction between the virus-encoded surface gp120 glycoprotein and cell surface CD4 molecules. Binding of gp120 to CD4 induces conformational changes in gp120 that result in the exposure of a chemokine receptor binding site on gp120. The subsequent interaction between gp120 and a chemokine receptor triggers the fusion of virus and cell membranes, allowing the delivery of the viral genome into the cytosol of the host cell. Based on this model, gp120 is responsible both for the initial attachment of the virus to target cells and the subsequent fusion with the host cell. For the last decade, CD4 has been thought to be the exclusive attachment receptor for HIV-1. Indeed, several observations support the notion that gp120-CD4 interactions are sufficient to mediate the initial attachment of HIV-1 to target cells (13). Specifically, it has been found that HIV-1 attaches to CD4-positive T cells but fails to attach to parental CD4-negative T-cell lines (33). Furthermore, anti-CD4 antibodies directed against the gp120 binding site of CD4 prevent HIV-1 attachment to CD4+ T cell lines (33). Finally, the apparent affinity between recombinant monomeric gp120 and soluble CD4 was found to be high, on the order of 1 to 10 nM (19). Altogether, these data led researchers to postulate that CD4 is the exclusive attachment receptor for HIV-1. However, recent data have emerged suggesting that interactions other than gp120-CD4 interactions are required for HIV-1 attachment to specific target cells. First, it has been found that the affinity of oligomeric gp120 for CD4 is much lower than the affinity for monomeric gp120 for CD4 (10, 20, 29). Specifically, oligomerization of patient virus gp120 into a trimer of gp120-gp41 heterodimers drastically reduces its affinity for CD4 by 3 logs (10). This apparent low affinity of oligomeric gp120 for CD4 suggested to us that the gp120-CD4 interaction alone would be not sufficient for tight attachment to cells which express little CD4, such as macrophages, microglia, and dendritic cells (9, 31). On such cell types, the attachment of patient virus with low intrinsinc affinity for CD4 suggests the requirement for supplementary interactions, via receptors others than CD4. Corroborating this hypothesis, Mondor et al. showed that HIV-1 attaches to CD4-negative adherent HeLa cells as well as CD4-positive HeLa cells (18). Furthermore, they found that anti-CD4 antibodies, which were previously shown to block HIV-1 attachment to suspension T cells, did not prevent HIV-1 attachment to CD4-positive HeLa cells (18). These data suggest that the dependence of HIV-1 attachment to target cells on the gp120-CD4 interaction is highly cell type specific and may be replaced by other virus-receptor interactions. Several lines of evidence suggest that cell surface heparan sulfate (HS) proteoglycans (HSPGs) act as necessary HIV-1 attachment receptors on specific target cells. Specifically, it has been shown that soluble polyanions such as dextran sulfate, heparin, or heparan sulfate inhibit HIV-1 infection (18, 4, 24, 27). The fact that polyanionic compounds bind to basic residues suggests that HSPGs participate in the initial HIV-1 attachment to target cells. Given that these compounds possess the capacity to bind to basic residues located in the V3 loop of gp120 (27), which is also responsible for fusion, the use of soluble polyanionic compounds does not permit the distinction between inhibition of attachment and/or fusion. However, more direct evidence suggests that HSPGs participate exclusively in HIV-1 attachment to target cells. Specifically, the removal of cell surface polyanionic chains of proteoglycans using heparitinase totally abrogates both HIV-1 attachment to and infectivity of CD4-positive HeLa cells (18). Given that heparitinase does not affect cell surface CD4, these findings suggest that HSPGs may act as alternative attachment receptors for HIV-1 on specific target cells such as HeLa cells. Using a methodology which allows us to quantitatively distinguish the initial attachment from subsequent fusion, we analyzed HIV-1 attachment to primary cells. Specifically, we investigated the respective uses of the two candidate attachment receptors, CD4 and HSPGs, in HIV-1 attachment to CD4+ T lymphocytes and macrophages.
Databáze: OpenAIRE
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