CCR5
Encyclopedia
C-C chemokine receptor type 5, also known as CCR5, is a protein
that in humans is encoded by the CCR5 gene
. CCR5 is a member of the beta chemokine receptors family of integral membrane protein
s. The CCR5 protein has also recently been designated CD195 (signifying a cluster of differentiation
of cell surface molecules present on white blood cell
s).
In humans, the CCR5 gene location
is on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation
resulting in the genetic deletion
of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains
of HIV-1 infection.
which functions as a chemokine receptor
in the CC chemokine group
. The natural chemokine
ligands
that bind to this receptor are RANTES
(a chemotactic
cytokine
protein also known as CCL5) and macrophage inflammatory protein
(MIP) 1α and 1β (also known as CCL3
and CCL4
). CCR5 is predominantly expressed
on T cell
s, macrophage
s, dendritic cell
s and microglia
. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear.
most commonly uses CCR5 and/or CXCR4
as a co-receptor
to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. The normal ligand
s for this receptor, RANTES, MIP-1β
, and MIP-1α
, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection, suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.
A number of new experimental HIV drugs, called entry inhibitors
, have been designed to interfere with the interaction between CCR5 and HIV, including PRO140 (Progenics), Vicriviroc
(Schering Plough), Aplaviroc
(GW-873140) (GlaxoSmithKline
) and Maraviroc
(UK-427857) (Pfizer
). A potential problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist
of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. Development of Aplaviroc has been terminated due to safety concerns (potential liver toxicity).
CCR5-Δ32 is a deletion mutation of a gene that has a specific impact on the function of T cell
s. At least one copy of CCR5-Δ32 is found in about 10% of people of Northern Europe
and in those of Northern European descent
. It has been hypothesized that this allele
was favored by natural selection
during the Black Death
. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age
samples, at levels comparable to the modern European population. Smallpox
may be another candidate for the high level of the mutation in the European population.
The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis
was demonstrated in the laboratory not to associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus
infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies, indicating that not all of the functions of CCR5 may be compensated by other receptors.
While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV R5 entry; two copies of this allele provide strong protection against HIV infection. This allele is found in 5–14% of Europeans but is rare in Africans and Asians. CCR5-Δ32 decreases the number of CCR5 proteins on the outside of the CD4 cell, which can have a large effect on the HIV disease progression rates
. Multiple studies of HIV-infected persons have shown that presence of one copy of this allele delays progression to the condition of AIDS
by about two years. It is possible that a person with the CCR5-Δ32 receptor allele will not be infected with HIV R5 strains. Several commercial testing companies offer tests for CCR5-Δ32.
A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals. When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 over time take over the culture as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus resistant cell pool in infected individuals.
This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia
, and was treated with chemotherapy
to suppress the cancer. A bone marrow transplant containing stem cell
s from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with the CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues. Before the transplant, low levels of HIV X4
, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors. However, this is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4. After three years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.
Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.
with CCL5 and CCL3L1
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the CCR5 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. CCR5 is a member of the beta chemokine receptors family of integral membrane protein
Integral membrane protein
An integral membrane protein is a protein molecule that is permanently attached to the biological membrane. Proteins that cross the membrane are surrounded by "annular" lipids, which are defined as lipids that are in direct contact with a membrane protein...
s. The CCR5 protein has also recently been designated CD195 (signifying a cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
of cell surface molecules present on white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s).
In humans, the CCR5 gene location
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
is on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
resulting in the genetic deletion
Genetic deletion
In genetics, a deletion is a mutation in which a part of a chromosome or a sequence of DNA is missing. Deletion is the loss of genetic material. Any number of nucleotides can be deleted, from a single base to an entire piece of chromosome...
of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains
HIV tropism
HIV tropism refers to the cell type that the human immunodeficiency virus infects and replicates in. HIV tropism of a patient's virus is measured by the Trofile assay....
of HIV-1 infection.
Function
The CCR5 protein is a G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
which functions as a chemokine receptor
Chemokine receptor
Chemokine receptors are cytokine receptors found on the surface of certain cells, which interact with a type of cytokine called a chemokine. There have been 19 distinct chemokine receptors described in mammals...
in the CC chemokine group
CC chemokine receptors
CC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CC 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...
. The natural chemokine
Chemokine
Chemokines 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...
ligands
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
that bind to this receptor are RANTES
RANTES
Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. It is also known as RANTES .- Function :...
(a chemotactic
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
protein also known as CCL5) and macrophage inflammatory protein
Macrophage Inflammatory Protein
Macrophage Inflammatory Proteins belong to the family of chemotactic cytokines known as chemokines. Macrophage inflammatory protein-1 , MIP-1 and MIP-1 are chemokines crucial for immune responses towards infection and inflammation. In humans, there are two major forms, MIP-1α and MIP-1β that are...
(MIP) 1α and 1β (also known as CCL3
CCL3
Chemokine ligand 3 is a protein that in humans is encoded by the CCL3 gene.-Further reading:...
and CCL4
CCL4
Chemokine ligand 4, also known as CCL4, is a protein which in humans is encoded by the CCL4 gene.- Function :CCL4, also known as Macrophage inflammatory protein-1β is a CC chemokine with specificity for CCR5 receptors...
). CCR5 is predominantly expressed
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
on T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s and microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear.
HIV
HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
most commonly uses CCR5 and/or CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
as a co-receptor
Co-receptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. The normal ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s for this receptor, RANTES, MIP-1β
CCL4
Chemokine ligand 4, also known as CCL4, is a protein which in humans is encoded by the CCL4 gene.- Function :CCL4, also known as Macrophage inflammatory protein-1β is a CC chemokine with specificity for CCR5 receptors...
, and MIP-1α
CCL3
Chemokine ligand 3 is a protein that in humans is encoded by the CCL3 gene.-Further reading:...
, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection, suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.
A number of new experimental HIV drugs, called entry inhibitors
Entry inhibitors
Entry inhibitors, also known as fusion inhibitors, are a class of antiretroviral drugs, used in combination therapy for the treatment of HIV infection. This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell...
, have been designed to interfere with the interaction between CCR5 and HIV, including PRO140 (Progenics), Vicriviroc
Vicriviroc
Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy...
(Schering Plough), Aplaviroc
Aplaviroc
Aplaviroc is a CCR5 entry inhibitor developed for the treatment of HIV infection. It is developed by GlaxoSmithKlineIn October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns...
(GW-873140) (GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
) and Maraviroc
Maraviroc
Maraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.-Mechanism of action:...
(UK-427857) (Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
). A potential problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. Development of Aplaviroc has been terminated due to safety concerns (potential liver toxicity).
CCR5-Δ32
CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a genetic variant of CCR5.CCR5-Δ32 is a deletion mutation of a gene that has a specific impact on the function of T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s. At least one copy of CCR5-Δ32 is found in about 10% of people of Northern Europe
Northern Europe
Northern Europe is the northern part or region of Europe. Northern Europe typically refers to the seven countries in the northern part of the European subcontinent which includes Denmark, Estonia, Latvia, Lithuania, Norway, Finland and Sweden...
and in those of Northern European descent
European ethnic groups
The ethnic groups in Europe are the various ethnic groups that reside in the nations of Europe. European ethnology is the field of anthropology focusing on Europe....
. It has been hypothesized that this allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
was favored by natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
during the Black Death
Black Death
The Black Death was one of the most devastating pandemics in human history, peaking in Europe between 1348 and 1350. Of several competing theories, the dominant explanation for the Black Death is the plague theory, which attributes the outbreak to the bacterium Yersinia pestis. Thought to have...
. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age
Bronze Age
The Bronze Age is a period characterized by the use of copper and its alloy bronze as the chief hard materials in the manufacture of some implements and weapons. Chronologically, it stands between the Stone Age and Iron Age...
samples, at levels comparable to the modern European population. Smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...
may be another candidate for the high level of the mutation in the European population.
The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis
Yersinia pestis
Yersinia pestis is a Gram-negative rod-shaped bacterium. It is a facultative anaerobe that can infect humans and other animals....
was demonstrated in the laboratory not to associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus
West Nile virus
West Nile virus is a virus of the family Flaviviridae. Part of the Japanese encephalitis antigenic complex of viruses, it is found in both tropical and temperate regions. It mainly infects birds, but is known to infect humans, horses, dogs, cats, bats, chipmunks, skunks, squirrels, domestic...
infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies, indicating that not all of the functions of CCR5 may be compensated by other receptors.
While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV R5 entry; two copies of this allele provide strong protection against HIV infection. This allele is found in 5–14% of Europeans but is rare in Africans and Asians. CCR5-Δ32 decreases the number of CCR5 proteins on the outside of the CD4 cell, which can have a large effect on the HIV disease progression rates
HIV Disease Progression Rates
Following infection with HIV-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics and immune function, health care and co-infections as well as viral genetic variability may affect the rate of progression to AIDS.-Rapid progressors:A...
. Multiple studies of HIV-infected persons have shown that presence of one copy of this allele delays progression to the condition of AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
by about two years. It is possible that a person with the CCR5-Δ32 receptor allele will not be infected with HIV R5 strains. Several commercial testing companies offer tests for CCR5-Δ32.
A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals. When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 over time take over the culture as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus resistant cell pool in infected individuals.
This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia
Myeloid leukemia
Myeloid leukemia is a type of leukemia affecting myeloid tissue.Types include:* Acute myeloid leukemia* Chronic myelogenous leukemia...
, and was treated with chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
to suppress the cancer. A bone marrow transplant containing stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with the CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues. Before the transplant, low levels of HIV X4
HIV tropism
HIV tropism refers to the cell type that the human immunodeficiency virus infects and replicates in. HIV tropism of a patient's virus is measured by the Trofile assay....
, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors. However, this is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4. After three years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.
Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.
Interactions
CCR5 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with CCL5 and CCL3L1
CCL3L1
Chemokine ligand 3-like 1, also known as CCL3L1, is a protein which in humans is encoded by the CCL3L1 gene.-Function:This gene is one of several chemokine genes clustered on the q-arm of chromosome 17. Chemokines are a family of secreted proteins involved in immunoregulatory and inflammatory...
.
See also
- Discovery and development of CCR5 receptor antagonistsDiscovery and development of CCR5 receptor antagonistsCCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the HIV entry process...
- Entry inhibitor
- HIV tropismHIV tropismHIV tropism refers to the cell type that the human immunodeficiency virus infects and replicates in. HIV tropism of a patient's virus is measured by the Trofile assay....
- maravirocMaravirocMaraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.-Mechanism of action:...
External links
- Video and text from a PBS documentary about the discovery of CCR5
- HuGENavigator literature on HIV Infections and CCR5 from CDCCenters for Disease Control and PreventionThe Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
- (note, authors may not be CDC employees, and there is no public domain notice on the page, so this cannot be assumed to be public domainPublic domainWorks are in the public domain if the intellectual property rights have expired, if the intellectual property rights are forfeited, or if they are not covered by intellectual property rights at all...
) - Schering-Plough Initiates Phase III Studies with CCR5-Vicriviroc in Treatment- Experienced HIV Patients.