CCR5 gene

The CCR5 gene (CCR5 stands for: C-C Motif Chemokine Receptor 5) is a protein-coding gene located on chromosome 3p21.31. An important paralog of this gene is CCR2.

The CCR5 gene encodes a member of the beta-chemokine receptor family, which is thought to be a "seven-transmembrane protein" similar to G protein-coupled receptors. The CCR5 gene is located in the chemokine receptor gene cluster region. An allelic polymorphism in this gene results in both functional and non-functional alleles; the reference genome represents the functional allele. Two transcript variants encoding the same protein have been found for this gene.

The receptor protein encoded by this gene is expressed by T cells and macrophages and is known to be an important co-receptor for the entry of macrophage-tropic viruses, including HIV, into host cells. Defective alleles of this gene have been associated with resistance to HIV infection. Ligands of this receptor include monocyte chemoattractant protein 2 (MCP-2), macrophage-inflammatory protein 1 alpha (MIP-1 alpha), macrophage-inflammatory protein 1 beta (MIP-1 beta) and regulated protein expressed and secreted upon activation of normal T cells (RANTES). The expression of this gene was also detected in a promyeloblast cell line, suggesting that this protein may play a role in the proliferation and differentiation of the granulocyte lineage.

The encoded protein acts as a receptor for a number of pro-inflammatory CC chemokines, including CCL3/MIP-1-alpha, CCL4/MIP-1-beta and RANTES. It then transmits a signal by increasing intracellular calcium ion levels. The receptor protein may play a role in controlling the proliferation or differentiation of the granulocytic lineage. It participates in T lymphocyte migration to the site of infection by acting as a chemotactic receptor (Sharapova TN et al. 2018).

Another important discovery was that members of the chemokine receptor family serve as cofactors for HIV entry into cells. It was discovered early on that allelic polymorphisms in the CCR5 gene, which codes for the CCR5 chemokine receptor, exert a significant influence on HIV susceptibility and disease progression of HIV infections. The CCR5 protein acts as a coreceptor (CD4 is the primary receptor) of the Human Immunodeficiency Virus-1/HIV-1 (McNicholl JM et al. 1997).

Gene therapy approaches in which haematopoietic stem cells are used to generate an HIV-resistant immune system have proven successful in the past. Deletion of the HIV coreceptor CCR5 has proven to be a viable strategy. One risk here is a co-receptor switch to CXCR4 (Mehmetoglu-Gurbuz T et al. 2021).

Only recently it became known that a Chinese biophysicist used the Cripr technique to induce a heritable mutation in the CCR5 gene. This was intended to make the twins born in the meantime and their possible offspring resistant to the Hi virus. What actually occurred was genetic mosaicism in both girls. Some of the twins' somatic cells contain the intended genetic mutation, while others do not. In addition, unintended target effects occurred, i.e. genetic changes that affected the target gene but other DNA segments.

1. Mehmetoglu-Gurbuz T et al. (2021) Combination gene therapy for HIV using a conditional suicidal gene with CCR5 knockout. Virol J 18:3
2. McNicholl JM et al. (1997) Host genes and HIV: the role of the chemokine receptor gene CCR5 and its allele. Emerg Infect Dis 3:261-271.
3. Sharapova TN et al. (2018) Tag7-Mts1 Complex Induces Lymphocytes Migration via CCR5 and CXCR3 Receptors. Acta Naturae 10:115-120.)