It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, the functional response of the receptor, and HIV co-receptor activity. Modulation of CCR5 activity contributes to a non-pathogenic course of infection with
simian immunodeficiency virus (SIV) in several African non-human primate species that are long-term natural hosts of SIV and avoid immunodeficiency upon the infection. These regulatory mechanisms include: genetic deletions that abrogate cell surface expression of CCR5, downregulation of CCR5 on the surface of CD4+ T cells, in particular on memory cells, and delayed onset of CCR5 expression on the CD4+ T cells during development.
HIV HIV-1 most commonly uses the chemokine receptors CCR5 and/or
CXCR4 as
co-receptors to enter target immunological cells. These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell. The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell. The co-receptor also recognizes the V1-V2 region of gp120 and the bridging sheet (an antiparallel, 4-stranded β sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity. 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. CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, released from its metastable conformation and inserted into the membrane of the host cell. Although it has not been confirmed, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine-sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains. Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function. A number of new experimental HIV drugs, called
CCR5 receptor antagonists, have been designed to interfere with binding between the Gp120 envelope protein and the HIV co-receptor CCR5. Even without the availability of either co-receptor (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail) that resulted in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.
Cancer CCR5 inhibitors blocked the migration and metastasis of breast and prostate cancer cells that expressed CCR5, suggesting that CCR5 may function as a new therapeutic target. Recent studies suggest that CCR5 is expressed in a subset of cancer cells with characteristics of cancer stem cells, which are known to drive therapy resistance, and that CCR5 inhibitors enhanced the number of cells killed by current chemotherapy. Expression of CCR5 is induced in breast and prostate epithelial cells upon transformation. In preclinical studies of immune competent mice CCR5 inhibitors blocked metastasis to the bones and brain. A Phase 1 clinical study of a CCR5 inhibitor in heavily pretreated patients with metastatic colon cancer demonstrated an objective clinical response and reduction in metastatic tumor burden.
Stroke Increased levels of CCR5 are part of the inflammatory response to stroke and death. Blocking CCR5 with
Maraviroc (a drug approved for HIV) may enhance recovery after stroke. In the developing brain, chemokine receptors such as CCR5 influence neuronal migration and connection. After stroke, they seem to decrease the number of connection sites on neurons near the damage. Individuals homozygous for this mutation (Δ32/Δ32) lack functional CCR5 on cell surfaces and exhibit strong resistance to HIV-1 infection, This mutation has also influenced therapeutic strategies, including gene-editing approaches aimed at mimicking its HIV-resistant phenotype. == See also ==