Attachment Receptors and Hot Spots for HIV Infection

By Jason Socrates Bardi

In the world of human immunodeficiency virus (HIV) research, much of the focus for the last couple of decades has been on the host receptors that are necessary for the entry of HIV into the cell—the CD4 receptor and its co-receptor CCR5, for instance, which HIV uses to enter helper T cells.

So much attention has been given to these CD4 receptors, in fact, that they have become almost synonymous with HIV itself. Loss of CD4 receptors has long been a defining diagnostic of AIDS, and the level of CD4 cells is a marker of disease progression.

However, this is only the start of the story. There are also "attachment" receptors, which have been shown in recent years to enhance the entry of HIV into cells.

"Now more than ever, there is a growing body of knowledge that suggests attachment receptors can have a profound impact on HIV pathogenesis," says Assistant Professor Philippe Gallay, who is a member of the Department of Immunology at The Scripps Research Institute (TSRI). In his laboratory, Gallay looks at the attachment of the virus to cells and looks toward using those host proteins as a guide for drug design.

Hooked on Sugars

The particular class of attachment receptor that interests Gallay consists of long, extended proteins on the surface of human cells that are decorated with a kind of sugar known as heparin sulfate chains. Heparin sulfate chains are attached to "glyco" proteins on the surface of cells like macrophages, which use them for a number of biological reasons, like binding to cytokines and growth factors in the bloodstream.

Gallay and his colleagues showed a few years ago that these heparin sulfate chains are also important players in the pathology of HIV because cells that are decorated with these heparin sulfate chains are like glue for the virus. Heparin sulfate chains have affinity for the viral coat protein GP120 on HIV, and HIV seems to use them to gain entry into cells like macrophages, one of the virus's main target cells.

"When you remove these sugars, the virus cannot infect macrophages," says Gallay, who demonstrated this a few years ago in a study with Research Associate Andrew C. S. Saphire.

But the sugars are only part of the story. Recently, Gallay and members of his laboratory published a paper describing the primary importance of a human protein called syndecan, which contains certain "motifs" of amino acids that the body's heparin sulfate chains attach to, which in turn interact with HIV's viral coat protein GP120. The group that published this finding included Michael D. Bobardt, Saphire, Hsiu-Cheng Hung, and Xiaocong Yu at TSRI and their colleagues Bernadette Van der Schueren, Zhe Zhang, and Guido David of the Center for Human Genetics at the University of Leuven and Flanders Interuniversity Institute in Belgium.

HIV CoOpts the Machinery of the Cell

Syndecans are actually a family of four different highly conserved transmembrane proteins that sit on the outside of cells. While no syndecan structures have been solved yet, their extracellular domains are known to extend from the cell surface, and at their terminus, they usually have motifs to which heparin sulfate chains are covalently attached.

Syndecans are the connection between the cells and the extracellular matrix, the molecular scaffold the body uses to build collections of cells into tissues. The interaction of syndecans with extracellular matrix components induces signals inside cells that are related to adhesion and migration. Cells that are adhering to the extracellular matrix express high levels of syndecans, while T cells and other mobile cells that do not adhere to the extracellular matrix do not express syndecans.

"They [Syndecans] probably have several biological roles," says Gallay, "such as presenting cytokines and growth factors to receptors."

Significantly, this machinery that binds to cytokines and growth factors in the bloodstream is what HIV has hijacked for its own purposes. It tricks the syndecans into capturing virions rather than growth factors.

"We found that syndecans can capture a lot of virus via their long extended chains," says Gallay. He had previously shown that syndecans are expressed on the surface of macrophages and that, by removing the syndecans, they were able protect the macrophages from infection. He also showed that monocytes, the precursor cells from which macrophages are derived, do not express syndecans and cannot be infected with HIV, whereas macrophages do express syndecans and can be infected. So syndecans, because of the affinity of their heparin sulfate chains for GP120, can be used by HIV to gain entry into cells.

But there is more. In his recent study, published in the January 2003 issue of the journal Immunity, Gallay and his colleagues showed that syndecans could act as in trans receptors, meaning that cells decorated with syndecans not only capture HIV, they help it to infect other cells that do not express the syndecans.

In other words, the presence of syndecans on one cell can help HIV enter another cell.


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Assistant Professor Philippe Gallay (left) and Research Associate Andrew C. S. Saphire examine a gel. Photo by Michael Balderas.













This drawing illustrates the interaction between HIV and heparin sulfate chains on the surface of human cells. Courtesy Peggy Myer, Biomedical Graphics.Click to enlarge.