Understanding the infection mechanisms of the Human Immunodeficiency Virus (HIV) is a global health priority. Central to this process is a protein named C-C chemokine receptor type 5, or CCR5. This protein, found on the surface of human immune cells, plays a role in how HIV gains entry into the very cells meant to protect the body. Exploring this interaction reveals the basis for natural resistance and has illuminated pathways for advanced medical treatments.
The Biological Role of CCR5
C-C chemokine receptor type 5 is a protein that functions as a receptor for signaling molecules known as chemokines. These receptors are located on the outer membranes of various immune cells, including T-lymphocytes, macrophages, and dendritic cells. The placement of CCR5 on these cells allows it to play a direct part in coordinating immune responses.
The normal purpose of CCR5 is to help direct the immune system’s response to infection and injury. When tissues become inflamed, they release specific chemokines that bind to CCR5 receptors on circulating immune cells. This binding acts as a chemical signal that guides the cells to the site of inflammation, a process called chemotaxis.
Once activated by its chemokine ligands, CCR5 initiates intracellular signals that mediate the immune response. This involves cell migration, the activation of lymphocytes, and the regulation of T-cell differentiation. In this way, the CCR5 protein functions as a communication hub, helping to direct immune traffic to where defensive cells are most needed.
How HIV Exploits CCR5 for Infection
Many strains of HIV, especially those that establish the initial infection, are categorized as R5-tropic, meaning they rely on the CCR5 protein to enter host cells. The process of viral entry begins when a protein on HIV’s surface, glycoprotein 120 (gp120), attaches to the primary receptor on an immune cell, a protein called CD4. This initial binding is the first step of the infection.
The docking of gp120 to the CD4 receptor induces a change in the shape of the gp120 protein. This exposes a previously hidden part of the viral protein, which is then able to bind to the CCR5 receptor. The CCR5 protein functions as a co-receptor, and this dual engagement with both CD4 and CCR5 triggers the final stage of entry for R5-tropic strains.
This sequential binding brings the viral envelope into close proximity with the host cell’s membrane. It facilitates the action of another HIV protein, gp41, which fuses the two membranes. Once fused, the virus releases its genetic material into the host cell, hijacking its machinery to replicate and produce new viral particles.
By using the receptors that immune cells rely on for their normal function, HIV turns the body’s defense mechanisms into a gateway for its own propagation. This exploitation of the CCR5 co-receptor is a primary reason HIV is so effective at establishing a persistent infection and damaging the immune system.
The CCR5-Delta32 Mutation and HIV Resistance
A naturally occurring genetic variation, CCR5-delta32 (CCR5-Δ32), provides resistance against HIV. This mutation is a 32-base-pair deletion in the gene that codes for the CCR5 protein. This deletion leads to the production of a truncated and non-functional version of the protein that is not transported to the surface of immune cells.
Individuals who inherit this mutated gene from both parents are homozygous for the mutation. Because their immune cells lack surface CCR5, R5-tropic strains of HIV cannot bind after docking with CD4. This blocks the viral entry process, making these individuals highly resistant to the most common strains of HIV. The absence of health defects in people with this mutation suggests CCR5 is not essential for a healthy immune system.
Individuals who are heterozygous, meaning they have inherited one normal and one mutated gene copy, produce a reduced amount of functional CCR5 on their cell surfaces. While not completely immune, they often experience a slower progression of the disease if infected. The lower density of CCR5 co-receptors on their cells makes viral entry less efficient.
The prevalence of the CCR5-delta32 mutation varies among global populations. It is most frequent in people of Northern European descent, where up to 10% may be heterozygous. The mutation is much rarer in people of African, Asian, and Native American ancestry, leading to hypotheses that it was selected for in European populations due to past epidemics.
CCR5-Targeted HIV Therapies
The natural resistance conferred by the CCR5-delta32 mutation inspired therapies that target this co-receptor. One class of these drugs is CCR5 antagonists, also known as entry inhibitors. The medication Maraviroc works by binding to the CCR5 receptor and changing its shape. This prevents the HIV gp120 protein from binding to it, even after attaching to CD4.
This mechanism blocks the entry of R5-tropic HIV strains. Before a patient is prescribed a CCR5 antagonist, a tropism test must determine if their viral strain uses CCR5. These drugs are ineffective against strains of HIV that use a different co-receptor, CXCR4, or both.
Advanced therapeutic strategies aim to replicate the effects of the CCR5-delta32 mutation through gene editing. This approach involves modifying a patient’s own cells to disable the CCR5 gene. Technologies like CRISPR-Cas9 are explored to edit the gene in hematopoietic stem cells, which produce all other blood and immune cells. The goal is to create a population of immune cells that lack functional CCR5, making them resistant to HIV.
This concept was demonstrated in the case of the “Berlin Patient,” Timothy Ray Brown, who had both leukemia and HIV. He received a stem cell transplant from a donor homozygous for the CCR5-delta32 mutation. The transplant treated his cancer and led to his HIV remission, as his new immune system was resistant to the virus. While stem cell transplants are too risky for widespread use, this case provided a proof-of-concept for curative strategies targeting CCR5.