CCR5
Based on Wikipedia: CCR5
The Genetic Mutation That Makes You Immune to HIV
About one percent of people with European ancestry carry a broken gene. Not broken in a bad way—broken in a way that might save their lives. They're missing thirty-two letters of genetic code from a gene called CCR5, and that tiny deletion makes them essentially immune to the most common strains of HIV.
To understand why, you need to understand how HIV gets into your cells in the first place. And that story involves molecular deception, evolutionary arms races, and a protein that sits on the surface of your immune cells like a doorway waiting to be picked.
The Doorway HIV Uses
CCR5 stands for C-C chemokine receptor type 5. That's a mouthful, but the basic idea is straightforward: it's a receptor protein that sticks out from the surface of white blood cells. Under normal circumstances, it acts as a docking station for chemokines—small signaling molecules that help coordinate your immune response. When inflammation breaks out somewhere in your body, chemokines float through your bloodstream like chemical distress signals, and CCR5-bearing cells follow the gradient to the site of trouble.
This is all perfectly reasonable cellular machinery. The problem is that HIV figured out how to hijack it.
The human immunodeficiency virus is covered in proteins called gp120 and gp41. These aren't chemokines—they don't have the right structure at all—but gp120 has evolved to mimic certain properties of chemokines well enough to bind to CCR5 anyway. It's molecular forgery. The virus shows up at the door wearing a disguise just convincing enough to get a foot inside.
The Two-Key Lock
HIV infection requires two separate binding events, like a safe that needs two keys turned simultaneously. First, the viral gp120 protein latches onto CD4, a different receptor on immune cells. CD4 is the virus's primary target, which is why the cells HIV infects are called CD4-positive T cells.
But binding to CD4 alone isn't enough. The virus needs a co-receptor to complete the process, and CCR5 is its favorite choice. After gp120 binds to CD4, it undergoes a shape change that exposes new regions—regions that can then grab onto CCR5. Only when both receptors are engaged does the viral membrane fuse with the cell membrane, allowing the virus to inject its genetic payload.
This two-step process explains a puzzling observation: in the early stages of HIV infection, the viruses you find are almost always CCR5-tropic, meaning they specifically use CCR5 as their co-receptor. Even in people who remain infected for years, at least half harbor only these CCR5-using strains. The virus apparently has a strong preference for this particular door.
What CCR5 Actually Looks Like
CCR5 belongs to a family called G protein-coupled receptors, or GPCRs. This is an enormous family—hundreds of members in humans—and they all share a distinctive architecture: seven spiral structures called alpha helices that weave back and forth through the cell membrane like a serpent threading through fabric.
Picture it this way. The receptor has parts that stick outside the cell (the extracellular side), parts embedded in the membrane, and parts that dangle inside the cell (the intracellular side). The external portions form a pocket where chemokines can dock. The transmembrane helices create a deep cavity that can also accommodate smaller molecules, including drugs. And the internal portions connect to signaling machinery that translates "something bound outside" into "do something inside."
The whole structure is held together by molecular bridges called disulfide bonds—sulfur atoms from different parts of the protein linked together like spot welds, preventing the receptor from flopping around into useless shapes.
The Delta-32 Mutation
Now here's where it gets interesting.
A small percentage of people, mostly of Northern European descent, carry a mutation called CCR5-delta-32. The "delta-32" means thirty-two base pairs—thirty-two letters of DNA—have been deleted from the CCR5 gene. This isn't a subtle typo. It's like removing a critical paragraph from the middle of a recipe. The resulting protein is so mangled that it never makes it to the cell surface at all.
If you inherit one copy of this mutant gene (from one parent), you still have some functional CCR5 from your other copy. You can still get HIV, but the infection progresses more slowly and your viral loads tend to be lower. The virus has fewer doors to knock on.
If you inherit two copies—one from each parent—you have no functional CCR5 whatsoever. And that means HIV simply cannot enter your cells through its preferred route. The R5 strains of HIV, which are the most common and the ones typically transmitted between people, bounce off your immune cells like a key in the wrong lock.
Living Without CCR5
You might wonder: if CCR5 is part of the immune system, wouldn't losing it entirely cause problems? Remarkably, people with two copies of the delta-32 mutation seem to be mostly fine. They live normal, healthy lives. This tells us that CCR5, whatever it does under normal circumstances, isn't strictly essential. Other receptors and signaling pathways apparently compensate for its absence.
There is one caveat. People lacking CCR5 appear to be more susceptible to certain flaviviruses, a family that includes West Nile virus and tick-borne encephalitis. The protective role CCR5 normally plays in these infections isn't fully understood, but its absence seems to impair some aspect of the immune response. Evolution rarely gives us something for nothing.
The Geography of Immunity
The delta-32 mutation is strikingly common in Northern Europe—reaching frequencies of ten percent or higher in some Scandinavian populations—but rare or absent elsewhere. This geographic pattern suggests the mutation was advantageous at some point in European history, spreading through the population under selective pressure from some infectious disease.
The obvious candidate might seem to be HIV, but that doesn't work chronologically. HIV only emerged in humans in the twentieth century, while the delta-32 mutation has been around for centuries, possibly millennia. Something else must have selected for it.
One popular hypothesis is the bubonic plague. The Black Death killed roughly a third of Europe's population in the fourteenth century, and CCR5 might have played some role in Yersinia pestis infection. But this theory remains controversial. Another candidate is smallpox, which ravaged European populations for centuries and might have used CCR5 or related pathways. The true selective agent may never be known with certainty.
From Mutation to Medicine
Understanding CCR5's role in HIV infection opened an obvious therapeutic avenue: what if we could block CCR5 in people who have it? If the virus needs this receptor to enter cells, preventing that interaction should stop infection in its tracks.
This is exactly what CCR5 antagonists do. The first one approved for clinical use was maraviroc, marketed as Selzentry by Pfizer. Approved in 2007, maraviroc binds to CCR5 and changes its shape just enough that HIV's gp120 protein can no longer recognize it. The door is still there, but the lock has been changed.
Several other CCR5 antagonists reached various stages of development—vicriviroc, aplaviroc, and PRO140 among them—though maraviroc remains the only one with full regulatory approval as of this writing.
There's an important limitation to this approach. HIV is a wily pathogen with a high mutation rate, and while CCR5 is its preferred co-receptor, it's not the only option. Some HIV strains use a different receptor called CXCR4 instead. If you block CCR5, you create selective pressure for the virus to switch doors. In practice, studies of viral resistance have shown that HIV often adapts by binding to different regions of CCR5 or binding more tightly, rather than switching to CXCR4 entirely. But the possibility remains.
The Berlin Patient and Beyond
The most dramatic application of CCR5 biology came not from a drug but from a bone marrow transplant. Timothy Ray Brown, known as the Berlin Patient, was an American living in Germany who had both HIV and leukemia. His leukemia required a bone marrow transplant, and his doctors made an unusual decision: they deliberately chose a donor who was homozygous for the delta-32 mutation.
The transplant replaced Brown's entire immune system with one that lacked functional CCR5. After the procedure, he stopped taking antiretroviral drugs—and remained HIV-free for the rest of his life. He was, by any reasonable definition, cured.
Brown's case proved that eliminating CCR5 could eliminate HIV, at least in principle. But bone marrow transplants are brutal procedures with significant mortality risk. You wouldn't undergo one just to treat HIV when antiretroviral drugs work perfectly well. The search continues for ways to achieve the same result more safely, including gene-editing approaches that aim to knock out CCR5 in a patient's own cells.
CCR5 and Cancer
HIV isn't the only disease where CCR5 matters. In a finding that surprised many researchers, CCR5 turns out to be involved in cancer metastasis—the process by which tumor cells spread from their original location to distant sites in the body.
Normal breast and prostate cells don't express CCR5 at all. But when these cells become cancerous, about half of breast cancers (particularly the aggressive triple-negative subtype) and a significant fraction of prostate cancers start producing the receptor. This isn't just a coincidence. The chemokine signals that normally guide immune cells seem to help guide cancer cells too, drawing them toward distant organs where they establish new tumors.
The therapeutic implication is straightforward: CCR5 antagonists like maraviroc, already approved for HIV, might be repurposed to prevent cancer spread. Early clinical studies have shown some promise. In one phase I trial, heavily pretreated patients with metastatic colon cancer showed objective clinical responses and reduced tumor burden when treated with a CCR5 inhibitor.
Some evidence also suggests that CCR5-expressing cancer cells have characteristics of cancer stem cells—the rare, therapy-resistant cells thought to drive tumor recurrence and treatment failure. If CCR5 inhibitors can target these cells specifically, they might enhance the effectiveness of conventional chemotherapy.
CCR5 and Stroke Recovery
In yet another unexpected twist, CCR5 appears to influence recovery from stroke.
When a stroke occurs, inflammatory responses surge in the brain. CCR5 levels increase as part of this inflammatory cascade, and blocking CCR5 with maraviroc seems to improve outcomes in animal models. The mechanism isn't fully understood, but in the developing brain, chemokine receptors like CCR5 help guide neurons as they migrate and form connections. After stroke damage, these same receptors may affect how surviving neurons reorganize—and not in a helpful way.
Studies suggest that CCR5 activity reduces the number of new synaptic connections that form near damaged tissue. Blocking it appears to allow more robust rewiring, potentially improving functional recovery. Human clinical trials exploring this application are underway.
The Bigger Picture
The CCR5 story illustrates several broader principles about biology and medicine.
First, evolution is a tinkerer, not an engineer. The same receptor that helps coordinate immune responses also serves as a viral entry point, influences cancer metastasis, and modulates stroke recovery. There's no grand design here—just molecular machinery being repurposed and exploited in different contexts.
Second, genetic variation in human populations often reflects past selective pressures we can only dimly perceive. The delta-32 mutation spread through Northern Europe for reasons we don't fully understand, creating a pool of HIV-resistant individuals long before HIV existed.
Third, understanding mechanism enables intervention. Once researchers figured out that CCR5 was HIV's co-receptor, they could design drugs to block it. Once they discovered cancer cells hijack CCR5 for metastasis, they could repurpose those same drugs for oncology. Each mechanistic insight opens new therapeutic possibilities.
And finally, biology rarely offers free lunches. The people immune to HIV are more susceptible to West Nile virus. The drugs that block one virus might enable another. Every intervention has consequences, and the art of medicine lies in finding interventions where the benefits outweigh the costs.
CCR5 is just one receptor among thousands, one small part of the staggeringly complex molecular machinery that makes up a human being. But its story touches on infectious disease, cancer, neurological damage, population genetics, and drug development. It's a reminder that even the smallest biological details can have profound implications for human health—if we take the time to understand them.