CCR5: A "Multi-Identity" Chemokine Receptor — From HIV Cure to Cancer Immunotherapy and Neural Repair, A Cross-Disciplinary Star Target!

1. CCR5/CCL5 and HIV Infection: From Molecular Mechanism to Gene Therapy

CCR5 is a seven-transmembrane G protein-coupled receptor (GPCR) belonging to the β-chemokine receptor family, primarily expressed on immune cells including T cells, macrophages, dendritic cells, and monocytes, with detectable expression in neurons and glial cells in the brain. Its natural ligands include chemokines such as CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), and CCL8 (MCP-2), which mediate directed migration of immune cells and calcium ion signal transduction, playing critical roles in immune surveillance, inflammatory responses, and cellular defense.

1.1 The "Gateway" for HIV Invasion

The reason CCR5 became a focus of HIV research stems from its function as a co-receptor for HIV-1 entry into host cells. After HIV-1 envelope glycoprotein gp120 binds to the CD4 molecule, it must further interact with CCR5 or CXCR4 to trigger viral membrane fusion and cell entry. Based on co-receptor preference, HIV-1 is classified into R5-tropic (using CCR5) and X4-tropic (using CXCR4) types. R5-tropic viruses are the dominant strains in early HIV infection and sexual transmission routes, accounting for over 80% of all infection cases.

This discovery explains why individuals carrying the CCR5Δ32 homozygous mutation have natural resistance to HIV-1 infection—a 32-base pair deletion causes premature termination of CCR5 gene transcription, expressing a truncated, non-functional receptor protein that viruses cannot use for cell invasion. This mutation has higher frequency in European populations (~10%) but is extremely rare in Asian and African populations.

1.2 The "Berlin Patient" and Functional Cure Milestone

In 2009, the famous "Berlin Patient" Timothy Brown became the world's first HIV functional cure case. He had both acute myeloid leukemia and HIV infection. After receiving a hematopoietic stem cell transplant from a donor carrying the CCR5Δ32 homozygous mutation, not only was his leukemia resolved, but HIV virus remained undetectable after discontinuing medication. This milestone case opened a new era of gene editing therapy for HIV.

To date, there have been 9 officially confirmed HIV cure cases globally, including the Berlin Patient, London Patient, Düsseldorf Patient, and others, all related to CCR5Δ32 mutation hematopoietic stem cell transplantation. These cases confirm that eliminating CCR5 function through gene editing or cell transplantation can achieve HIV functional cure.

1.3 Progress and Challenges in Gene Editing Therapy

CCR5 gene editing based on CRISPR/Cas9 technology has become a hot research direction for HIV treatment. A clinical study published in the New England Journal of Medicine by Professor Carl H. June's team at the University of Pennsylvania confirmed that CCR5 gene-modified autologous CD4+ T cell infusion therapy shows promise for controlling AIDS. The study showed that edited T cells can survive long-term in patients without serious adverse reactions.

However, CCR5 gene editing also faces important challenges:

• Viral strain preference differences: The dominant HIV strain in China is AE subtype (46%), which is X4-tropic; knocking out CCR5 cannot prevent infection by this strain
• Immune function impact: CCR5 plays important roles in immune defense against multiple viruses (influenza, tick-borne encephalitis virus, dengue, yellow fever)
• Potential cardiovascular risk: Animal experiments suggest CCR5 deficiency may increase cardiovascular disease risk

2. CCR5/CCL5 and Tumor Microenvironment Remodeling

In recent years, CCR5's role in the tumor microenvironment (TME) has received increasing attention. The CCR5/CCL5 axis profoundly influences tumor progression, metastasis, and treatment resistance by regulating immune cell infiltration, angiogenesis, and cancer stem cell maintenance.

2.1 Colorectal Cancer: Prognostic Prediction and Immune Evasion

Schlechter et al. published a study (2024) in the Journal for ImmunoTherapy of Cancer systematically analyzing the relationship between CCR5/CCL5 axis expression and patient prognosis in metastatic colorectal cancer. The study integrated CALGB/SWOG 80405 clinical trial data and large sample cohorts from the Caris NGS database, finding:

• Patients with low CCR5/CCL5 axis expression had significantly improved survival, especially in the chemotherapy plus cetuximab treatment group
• High CCR5/CCL5 axis expression correlates with multiple immunosuppressive cell infiltration: Regulatory T cells (Tregs), M1/M2 macrophages, myeloid-derived suppressor cells (MDSCs), tumor-associated fibroblasts (CAFs)
• High CCR5/CCL5 expression positively correlates with multiple immune checkpoint molecules: PD-1, PD-L1, PD-L2, CTLA-4, CD80, CD86, TIM-3, IDO1, LAG-3, etc.

This finding reveals the core role of the CCR5/CCL5 axis in tumor immune evasion: by recruiting immunosuppressive cells and upregulating immune checkpoint molecules, it constructs a "cold tumor" microenvironment that weakens anti-tumor immune responses.

2.2 Hepatocellular Carcinoma: A New Target for Radiosensitization

Chen et al. published a study (2025) in the Journal of Radiation Research that first revealed the core mechanism of CCR5 in radiotherapy resistance of liver cancer. The research team established an H22 tumor-bearing mouse model and found:

Core Findings:

• Radiotherapy induces tumor cells to secrete CCL5, promoting differentiation and migration of polymorphonuclear MDSCs (PMN-MDSCs)
• PMN-MDSCs inhibit CD8+ T cell proliferation and killing function through arginase and iNOS pathways
• Maraviroc combined with conventional fractionated radiotherapy (CFRT) significantly inhibits tumor growth, superior to radiotherapy or drug alone

Molecular Mechanism:

Maraviroc does not directly enhance radiation-induced tumor cell death, but rather blocks CCR5/CCL5 signaling, inhibiting PMN-MDSC differentiation from bone marrow progenitors, blocking their migration to the tumor microenvironment, and restoring T cell proliferation and cytotoxic function. This study provides important evidence for the "drug repurposing" strategy: the approved CCR5 antagonist Maraviroc can serve as a potential combination drug for radiosensitization in liver cancer.

2.3 Breast Cancer and Pancreatic Cancer: Double-Edged Sword of Metastasis Regulation

In breast cancer, CCR5/CCL5 axis expression is closely related to tumor progression and metastasis. Studies show:

• CCL5 can enhance proliferation and invasion of breast cancer cells
• CCR5 signaling promotes endothelial cell secretion of CCL5, inducing autophagy and promoting prostate cancer cell invasion
• Tumor-associated fibroblasts regulate CCL5 secretion through KLF5, activating cancer cell CCR5 to promote progression

In pancreatic cancer, CCR5-mediated MDSC infiltration is a key mechanism for immune evasion. Targeting CCR5 can reduce tumor-associated macrophage infiltration and remodel the anti-tumor immune microenvironment.

3. CCR5 and the Nervous System: A New Target for Stroke Recovery

CCR5's function in the nervous system was only revealed in recent years. In 2019, a breakthrough study published in Cell confirmed that CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury.

3.1 Research Findings

Neuroscientist Alcino Silva's team at UCLA discovered:

• Mouse model: Inhibiting CCR5 causes brain changes resulting in better memory and cognitive ability
• Stroke patient study: Patients carrying CCR5Δ32 mutation showed better recovery after neurological injury
• Mechanistic analysis: Activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy through CCR5 signaling, affecting neurodegenerative pathological processes

3.2 Clinical significance

CCR5 is the first gene discovered to be associated with human stroke recovery. Individuals carrying the CCR5Δ32 mutation are more likely to recover memory and cognitive function after stroke and traumatic brain injury.

3.3 Potential Risk Warning

This study also raised concerns about CCR5 gene editing safety:

• CCR5 deficiency may affect memory "forgetting" function, leading to excessive memory retention
• CCR5 plays important roles in antiviral immunity; deficiency may increase infection risk for influenza, tick-borne encephalitis, yellow fever, etc.
• CCR5-Δ32 carriers have 4 times higher risk of death from influenza than the general population

4. CCR5 and Autoimmune Diseases

The CCR5/CCL5 axis plays important roles in the inflammatory processes of multiple autoimmune diseases:

Studies show that CCR5 is highly expressed in active inflammatory bowel disease, positively correlating with lymphocyte grade and negatively correlating with β-arrestin2 expression. This suggests the potential value of CCR5 antagonists in autoimmune disease treatment.