CCR5

In one line: A 32-letter deletion in CCR5 makes some people resistant to HIV — and that accident of evolution gave us the first cure for HIV, a class of drugs, and the most notorious experiment in modern biology.

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The gene

CCR5 sits on the short arm of chromosome 3 (3p21.31). It builds a small receptor — a docking port that studs the surface of immune cells like T cells and macrophages — that normally reads the chemical signals of inflammation. Useful, but, as it happens, something the body can largely do without.

The mechanism

HIV doesn't break into a cell with one key. It needs two: the protein CD4, and then a co-receptor. For the strains that drive most new infections — the "R5-tropic" virus — that co-receptor is CCR5. The famous Δ32 allele is a 32-base-pair deletion that knocks the gene out of frame; the receptor comes out truncated and never reaches the cell surface. With no CCR5 on the door, R5 HIV has nowhere to dock. People with two broken copies are strongly resistant; people with one copy progress more slowly. The important caveat: a rarer "X4-tropic" virus uses a different door (CXCR4), so the protection is not absolute.

The hunt

In the mid-1990s, clinicians kept meeting people exposed to HIV again and again who never got infected. The phenotype came first (Paxton et al., Nature Medicine, 1996); the genotype followed within months, when several independent teams showed those people were Δ32 homozygotes (Liu et al., Cell; Samson et al., Nature; Dean & O'Brien et al., Science — all 1996). The deletion is common in Europe (~10% allele frequency, on a north–south cline) and nearly absent in African and East Asian populations.

The first cure

The discovery suggested an audacious move: rebuild someone's immune system out of CCR5-negative cells. In Berlin, Timothy Ray Brown had both HIV and leukemia; his physician Gero Hütter deliberately picked a bone-marrow donor homozygous for Δ32. Brown's HIV vanished, and he became the first person ever cured (he later died, in 2020, of recurrent leukemia — not HIV). A second man, Adam Castillejo, the "London Patient," was cured the same way. These transplants are a proof of principle, not a scalable therapy — they are brutal procedures justified only because each patient also needed a transplant for a blood cancer. (One later case, the "Geneva Patient," even reached remission with an ordinary CCR5 donor, complicating the simple story.)

The line that was crossed

In 2018, the biophysicist He Jiankui used CRISPR to disable CCR5 in human embryos and implanted them, producing twin girls — pseudonyms Lulu and Nana — the first gene-edited humans, with a third child following in 2019. He announced it at the Second International Summit on Human Genome Editing in Hong Kong, to immediate, near-universal condemnation. The crucial, widely-misreported fact: he did not recreate the protective Δ32 deletion. The CRISPR edits were new, untested mutations, different in each twin and mosaic from cell to cell — at least one twin was edited on only one of two copies — so even the intended "HIV resistance" was unproven. And the experiment was medically pointless: sperm washing already prevents an HIV-positive father from passing the virus to an embryo. A Chinese court convicted He of "illegal practice of medicine" in December 2019, sentencing him to three years in prison and a 3-million-yuan fine.

How CCR5 is used today

The honest path borrows the mutation, not the recklessness:

• A drug. Maraviroc (FDA-approved 2007) is a CCR5 antagonist — a small molecule that caps the receptor from the outside, mimicking what Δ32 does by accident (against R5-tropic virus only).
• Editing your own cells. Rather than a risky donor transplant, trials have edited a patient's own CD4 T cells ex vivo to disable CCR5 (Sangamo's zinc-finger approach; Tebas et al., NEJM 2014) — a safety proof of concept, not yet a cure.
• Beyond HIV. Strikingly, CCR5 also acts as a brake on brain plasticity: blocking it improves recovery after stroke and traumatic brain injury in models, and human Δ32 carriers recover better after stroke (Joy et al., Cell 2019). This is an active frontier, not settled medicine.

Sources

Full claim-by-claim evidence is in references.md. Primary anchors:

• Liu et al., Cell 1996; Samson et al., Nature 1996; Dean et al., Science 1996 — Δ32 and HIV resistance.
• Gupta et al., Nature 2019 / Lancet HIV 2020 — the London Patient; Hütter (Berlin Patient).
• MIT Technology Review (leaked-manuscript analysis, 2019); Ryder, The CRISPR Journal 2019 — what He Jiankui actually edited.
• Pfizer/FDA 2007 (maraviroc); Tebas et al., NEJM 2014; Joy et al., Cell 2019.

Accuracy note: This episode carefully states three things that popular coverage routinely gets wrong — (1) Δ32 blocks the R5-tropic virus, not all HIV; (2) "~1 in 10" is the allele frequency in Europeans, not the share of immune people; and (3) He Jiankui did not recreate Δ32 — his edits were novel, mosaic, and unproven. It also avoids a retracted 2019 claim that Δ32 shortens lifespan.