CXCR4, (a
CXC chemokine ReceptorCXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane proteins since they span the...
), also called
fusin, is an alpha-
chemokineChemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes. This receptor is one of several chemokine receptors that
HIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid,...
isolates can use to infect CD4+ T cells. Traditionally, HIV
isolatesIsolates is a term used by students and educators in Human Development Family Studies and by researchers, to describe members of a study group, usually child through young adult, who do not actively participate in cliques or friendship groups...
that use CXCR4 are known as T-cell tropic isolates. Typically these viruses are found late in infection.
CXCR4, (a
CXC chemokine ReceptorCXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane proteins since they span the...
), also called
fusin, is an alpha-
chemokineChemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes. This receptor is one of several chemokine receptors that
HIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid,...
isolates can use to infect CD4+ T cells. Traditionally, HIV
isolatesIsolates is a term used by students and educators in Human Development Family Studies and by researchers, to describe members of a study group, usually child through young adult, who do not actively participate in cliques or friendship groups...
that use CXCR4 are known as T-cell tropic isolates. Typically these viruses are found late in infection. It is unclear whether the emergence of CXCR4-using HIV is a consequence or a cause of
immunodeficiencyImmunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Most cases of immunodeficiency are acquired but some people are born with defects in the immune system, or primary immunodeficiency...
.
CXCR4 is upregulated during the implantation window in natural and Hormone Replacement Therapy cycles in the endometrium, producing, in presence of a human
blastocystThe blastocyst is a structure formed in the early embryogenesis of mammals, after the formation of the morula, but before implantation. It possesses an inner cell mass , or embryoblast, which subsequently forms the embryo, and an outer layer of cells, or trophoblast, which later forms the placenta...
, a surface polarization of the CXCR4 receptors suggesting that this receptor is implicated in the adhesion phase of human
implantationImplantation is an event that occurs early in pregnancy in which the embryo adheres to the wall of uterus. At this stage of prenatal development, the embryo is a blastocyst...
.
CXCR4's
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
SDF-1 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell
quiescenceQuiescence is a Latin-derived English language noun referring to a state of being quiet, still, at rest, dormant, inactive. Its adjectival form is quiescent, for example "a quiescent mind."Quiescence may refer to:...
. Unusually for chemokines, SDF-1 and CXCR4 are a relatively "monogamous" ligand-receptor pair (other chemokines tend to use several different chemokine receptors in a fairly "promiscuous" manner). Because the interaction between SDF-1 and CXCR4 plays an important role in holding hematopoietic stem cells in the bone marrow, drugs that block the CXCR4 receptor appear to be capable of "mobilizing" hematopoietic stem cells into the bloodstream as peripheral blood stem cells. Peripheral blood stem cell mobilization is very important in hematopoietic stem cell transplantation (as a recent alternative to transplantation of surgically-harvested
bone marrowBone marrow is the flexible tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells. It constitutes 4% of total body weight, i.e...
) and is currently performed using drugs such as G-CSF. G-CSF is a growth factor for neutrophils (a common type of white blood cells), and may act by increasing the activity of neutrophil-derived proteases such as neutrophil elastase in the bone marrow leading to proteolytic degradation of SDF-1. AMD3100 is an investigational drug, not yet in routine clinical use, which directly blocks the CXCR4 receptor: it appears to be a very efficient inducer of hematopoietic stem cell mobilization in animal and human studies.
Further reading