The C-C chemokine receptor type 5, known as CCR5, is a protein found on the surface of various immune cells, including T-cells and macrophages. A specific, naturally occurring genetic alteration in the gene that codes for this protein, referred to as the $\Delta 32$ mutation, offers a natural form of protection against certain pathogens. This mutation is of significant interest in medicine, most notably concerning the human immunodeficiency virus (HIV).
The Role of CCR5 in the Immune System
The CCR5 protein is a chemokine receptor, meaning it binds to small signaling proteins called chemokines, such as CCL3, CCL4, and CCL5. These chemokines act as chemical signals to guide white blood cells through the body.
The CCR5 receptor is particularly involved in chemotaxis, the process by which immune cells are directed toward sites of inflammation or infection. By binding its specific chemokines, CCR5 helps mobilize white blood cells, including T-cells and monocytes, out of the bloodstream and into the tissues where an immune response is needed.
Activating the receptor also contributes to the coordination of the cellular immune response, promoting the proliferation and function of T-cells. Individuals who lack a functional CCR5 receptor, due to the $\Delta 32$ mutation, generally exhibit normal immune function, suggesting other pathways can compensate for its absence in most situations.
The Delta 32 Mutation and HIV Resistance
The $\Delta 32$ mutation is a specific genetic alteration characterized by a 32-base pair deletion within the CCR5 gene sequence. This deletion causes a frameshift, resulting in the premature termination of protein synthesis. The resulting protein is truncated, misfolded, and never successfully transported to the surface of the immune cell.
The absence of a functional CCR5 receptor on the cell surface is the mechanism that confers resistance to HIV. The most common strains of HIV, known as R5-tropic viruses, require two specific molecules to enter a CD4+ T-cell: the primary CD4 receptor and the CCR5 co-receptor. The virus must bind to both in a precise sequence to fuse with the cell membrane and begin the infection process.
Without a functional CCR5 co-receptor, the R5-tropic HIV virus cannot successfully dock onto the cell’s surface. Individuals who inherit two copies of the mutated gene (homozygous carriers) do not express any functional CCR5 protein and are highly resistant to R5-tropic HIV infection.
Individuals who inherit the mutation from only one parent (heterozygous carriers) possess one normal and one mutated copy of the gene. They express a reduced number of functional CCR5 receptors, which provides some protection, resulting in a slower progression to AIDS and reduced viral loads if they become infected.
Geographic Distribution and Evolutionary History
The $\Delta 32$ allele is not uniformly distributed across the global population. The highest prevalence is found in populations of Northern European descent, with allele frequencies reaching up to 16% in some regions. The frequency decreases significantly across Europe and is virtually absent in African and East Asian populations.
The high frequency in Northern Europe suggests the allele was subjected to intense positive selection. Since HIV is a relatively modern pathogen, it could not have been the original selective pressure. Population genetic models estimate the age of the $\Delta 32$ mutation to be between 700 and 3,500 years old, with some evidence suggesting an even earlier origin.
A historical epidemic disease that utilized the CCR5 receptor for cell entry likely provided the selective advantage. Smallpox is a frequently cited candidate, as are certain viral hemorrhagic fevers or the bubonic plague, caused by the bacterium Yersinia pestis. Individuals carrying the $\Delta 32$ mutation would have been protected or experienced milder disease from this ancient pathogen.
Therapeutic Applications and Gene Editing
The CCR5 $\Delta 32$ mutation has served as a blueprint for developing curative strategies for HIV. The most compelling evidence comes from patients, including the “Berlin Patient” and the “London Patient,” who were cured of HIV after receiving allogeneic hematopoietic stem cell transplants. These patients, who had co-occurring cancers, received stem cells from donors naturally homozygous for the $\Delta 32$ mutation.
The transplant procedure replaced the patients’ HIV-susceptible immune systems with a new, HIV-resistant one. This procedure is complex, involves significant risk, and is only available to patients who require a stem cell transplant for another condition. The rarity of suitable $\Delta 32$ homozygous donors also limits its widespread application.
Researchers are now focusing on gene editing techniques to mimic the natural mutation in a patient’s own cells. Technologies like CRISPR/Cas9 are being developed to precisely inactivate the CCR5 gene in T-cells and hematopoietic stem cells. The goal is to create a pool of HIV-resistant immune cells that can be infused back into the patient, offering a safer and more scalable path to functional HIV resistance without needing an external donor.