Re: which protien does gp120 (HIV virus) bind to on an immune cell and what...

The Human Immunodeficiency Virus (HIV) is a Lentivirus - a type of retrovirus. Like other Lentiviruses, HIV has a membrane envelope that is covered with many copies of a special docking protein called gp120: "gp" stands for "glycoprotein" - a protein with sugars attached to it; and "120" refers to its size, 120 kiloDaltons (~120,000 M.W.). As a docking protein, HIV uses gp120 to bind to target cells and begin the fusion of the cell and viral membranes. In all of the Lentiviruses, gp120 uses one cellular receptor for both binding and fusion - a fact that had eluded many AIDS researches until relatively recently and that is important in understanding the virus.

The HIV gp120 envelope protein targets chemokine receptors (If this isn't the answer you were expecting, read on!). Chemokines are defined as non-antibody proteins that attract and recruit immune cells to sites of inflammation. They can be thought of as specialized hormones that are used for communication between different cells of the immune system. There are different groups of chemokines*, and specific receptors that recognize members of each group. Receptors are proteins on the surfaces of cells that bind to specific molecules (termed "ligands") and convey this to the cell in some form of signal. Chemokine receptors are "7-transmembrane domain, G-protein- linked receptors" that are deeply embedded in the cell membrane with binding pockets at or slightly below the cell membrane surface. It has been shown experimentally that gp120 has affinity for several different chemokine receptors, but that gp120 has greatest affinity for (prefers to bind to) two specific chemokine receptors: CCR5 and CXCR4*.

At this point, many readers are saying, "that's not what I learned," "that can't be right." To calm the nerves of the informed, there is another, equally important, receptor that gp120 can bind to called CD4, a member of the Immunoglobulin superfamily of antibody-like proteins. "CD" stands for "clusters of differentiation" - the CD antigens were first indentified as markers on different immune cells that could be used to tell different cells apart; for example, the first 12 or so were found on one population of lymphocytes (T-cells), while the next set were found on another population of lymphocytes (B-cells). with refinements of techniques and deeper understandings of receptor proteins, it was determined that the fourth CD antigen (CD4) defined a specific subset of T-cells that were responsible for activating and moderating the rest of the immune system, such that these CD4-expressing (CD4+) T-cells were renamed "helper T- cells" (T_h). More than simply a marker, CD4 was shown to be essential for the function of these T_h cells: CD4 works in conjunction with the "T-cell Receptor" (TCRa/b) to recognize foreign materials on other immune cells and tell the T_h cell to activate an immune response. Without CD4, the T_h cells are unable to properly bind to these antigen- presenting immune cells, just as without T_h cells, these other immune cells cannot be activated. The HIV gp120 envelope protein binds directly to the CD4 antigen.

So why does gp120 bind to two completely different types of proteins - one looking like an antibody, and one embedded in the membrane - and how does this relate to HIV and AIDS? It turns out that as high as gp120's affinity is for chemokine receptors, the cells that express these receptors have so many other, larger, bulkier proteins decorating their membranes, that gp120 never sees the chemokine receptors through this forest. One of the trees in the forest is CD4, which gp120 can see. By binding to CD4, gp120 is able to move the HIV virion close enough to the cell membrane for gp120 to eventually interact with the chemokine receptor of its choosing. It has been shown that viral invasion requires the clustering of these chemokine receptors, and the proximity the HIV virion gains from interacting with CD4 allows it to bring up to half of its surface gp120's adjacent to the membrane; creating a cluster of chemokine receptors as they interact with these proteins.

Now, let's take a step back. If HIV requires gp120 to bind to CD4 and then to either CCR5 or CXCR4, then cells expressing CD4 and one of these chemokine receptors should be targetted for HIV infection. In fact, CD4 is not specific to T_h cells but is also found on macrophages and dendritic cells. While dendritic cells have been shown to act as a reservoir for the virus in infected individuals, it was the discovery of HIV in macrophages that shifted researchers' understanding of the virus. Macrophages are the classic, amoba-like white blood cells that travel through the body eating foreign particles and attacking infections (Neutrophils do this too, but that's another story). Macrophages also act as antigen-presenting cells and can recruit T_h cells and more macrophages to sites of infection or inflammation. From the prespective of HIV, the biggest difference between macrophages and T_h cells is that macrophages express mostly CCR5, while T_h cells express mostly CXCR4. Moreover, the affinity of gp120 to each of these chemokine receptors is not equal: a specific set of amino acids in the binding pocket of gp120 determines whether it will bind to CCR5 or to CXCR4. This means that HIV virions can be divided into two "strains" according to the type of gp120 they possess: HIV with gp120 that binds preferentially to CCR5, found on macrophages, is called M-tropic; and HIV with gp120 that binds preferentially to CXCR4, found on T_h cells, is called T- tropic.

Here's the punchline: the M-tropic strain is virulent (and is responsible for the spread of the disease) and the T-tropic strain is not; however, the T-tropic strain causes loss of T_h cells (and thus causes AIDS) and the M-tropic strain does not! In fact, the initial HIV infection targets the macrophages, where the virus lives and propagates until it accrues enough mutations in the gp120 chemokine binding pocket to interact with CXCR4, at which point it becomes T-tropic and begins infecting T_h cells, resulting ultimately in AIDS. The most exciting outcome of this new understanding of the interplay between M- and T-tropism was the recent discovery of a hereditary mutation in the CCR5 gene (CCR5D32) that makes the carrier more resistant to HIV infection! Many groups are now looking at the specific interaction between the M-tropic gp120 and CCR5 to try to find a vaccine for HIV.

* Chemokines are grouped according to the presence of cysteine amino acid residues in a specific portion of the chemokine protein: with one cysteine, it's a "C Chemokine"; with two adjacent cysteines, it's a "CC Chemokine"; with two non-adjacent cysteines, it's a "CXC Chemokine". The receptors are named for the group of chemokines they bind followed by "R" for "Receptor" and a number to distinguish it from other, related receptors; hence, CCR5 is "CC Chemokine Receptor #5."