The human immune system defends the body against pathogens using specialized white blood cells known as T cells. To perform their duties, T cells use surface proteins called receptors to receive signals from their environment. These receptors act like antennas, allowing the cells to identify and respond to threats.
One such protein is the C-C chemokine receptor type 5, or CCR5. It is found on the surface of various immune cells, including certain T cells, and belongs to a large family of G protein-coupled receptors that span the cell membrane. The function of CCR5, and the consequences of its absence, are a significant area of scientific inquiry into immune function and disease.
The Normal Function of CCR5 on T Cells
In a healthy immune system, the CCR5 receptor’s primary role is managing T cell movement. As a chemokine receptor, it responds to signaling proteins called chemokines. When the body detects an injury or infection, it releases chemokines like CCL3, CCL4, and CCL5, which create a chemical trail for immune cells to follow.
The CCR5 receptor on a T cell detects these chemokines, guiding the cell from the bloodstream to the tissue or lymph node where it is needed. This process, known as chemotaxis, allows immune responders to gather at sites of inflammation. Other immune cells, including macrophages and dendritic cells, also use CCR5 to navigate to these areas.
CCR5 is also involved in T cell activation. When a T cell engages with an antigen-presenting cell, CCR5 is recruited to the point of contact, known as the immunological synapse. At this junction, the receptor helps deliver signals that enhance the T cell’s response, boosting its ability to multiply and release defensive molecules.
The Role of CCR5 in HIV Infection
The Human Immunodeficiency Virus (HIV) has co-opted the CCR5 receptor, turning it into a gateway for infection. HIV primarily targets CD4+ helper T cells, which orchestrate the immune response. To gain entry, a viral surface protein called gp120 first attaches to the main CD4 receptor on the T cell, which changes the gp120 protein’s shape, allowing it to bind to a coreceptor.
For the most common strains of HIV, this coreceptor is CCR5. The interaction between gp120, CD4, and CCR5 initiates the fusion of the viral and T cell membranes. This fusion allows the virus to inject its genetic material into the cell, starting the replication process.
Once inside, HIV hijacks the T cell’s machinery to produce thousands of new virus particles, which then bud from the cell to infect other CD4+ T cells expressing CCR5. This cycle of infection leads to the progressive destruction of CD4+ T cells. This destruction weakens the immune system and can eventually lead to Acquired Immunodeficiency Syndrome (AIDS).
The CCR5-Delta 32 Mutation
A naturally occurring genetic variation, the CCR5-delta 32 (CCR5-Δ32) mutation, provides a defense against HIV. This mutation is a deletion of 32 base pairs in the CCR5 gene, resulting in a truncated, nonfunctional receptor that does not reach the cell surface. Without the CCR5 receptor on the exterior of T cells, the entry point for the most common HIV strains is sealed.
A person’s resistance to HIV depends on the number of mutated gene copies they inherit. Heterozygous individuals, with one normal and one mutated copy, produce fewer functional CCR5 receptors. While they can still be infected, this often leads to a slower disease progression.
Homozygous individuals, who inherit a mutated copy from both parents, produce no functional CCR5 receptors. This makes them highly resistant to infection by R5-tropic HIV strains, which are responsible for most transmissions. The mutation is most common in populations of Northern European descent, occurring in about 10% of people.
Therapeutic Strategies Targeting CCR5
The discovery of CCR5’s role in HIV entry led to therapies designed to block this pathway. These strategies are centered on preventing the virus from using the receptor for entry.
Pharmacological Agents
One approach involves CCR5 antagonists, which are drugs that act as entry inhibitors. Maraviroc is an oral medication that binds to the CCR5 receptor and changes its shape, preventing the HIV gp120 protein from attaching. Another strategy uses monoclonal antibodies, like Leronlimab, which bind to CCR5 to obstruct the viral entry site.
Stem Cell Transplantation
A more definitive strategy is stem cell transplantation. The “Berlin Patient,” Timothy Ray Brown, was functionally cured of HIV after receiving a bone marrow transplant from a donor homozygous for the CCR5-Δ32 mutation. This procedure replaced his HIV-susceptible immune system with a genetically resistant one. This success has been replicated in other individuals, including Adam Castillejo, the “London Patient.”
Gene Editing
Building on this principle, researchers are exploring gene-editing technologies like CRISPR-Cas9 to modify a patient’s own cells. The goal is to disable the CCR5 gene in a patient’s hematopoietic stem cells or T cells. This would engineer an HIV-resistant immune system without needing a matched donor and is a promising area of clinical research.
Health Considerations Beyond HIV
While the absence of a functional CCR5 receptor protects against HIV, it is not without drawbacks. The receptor’s function is to guide immune cells to infection sites, and its absence can alter the body’s response to other pathogens.
Research shows that individuals homozygous for the CCR5-Δ32 mutation face an increased risk of severe illness from certain flaviviruses, such as West Nile Virus. The lack of CCR5 appears to impair the migration of protective T cells into the central nervous system. This hinders the body’s ability to control the viral infection in the brain.
Evidence also suggests a link between CCR5 deficiency and the severity of other viral infections. For example, patients with the CCR5-Δ32 mutation had a higher mortality rate during the 2009 influenza pandemic. Blocking or eliminating CCR5 as a therapy for HIV requires careful consideration of its broader role in host defense.