Legacy of a magic gene— CCR5- ∆ 32 : From discovery to clinical benefit in a generation

Abstract

The discovery of the 32-bp deletion allele of the chemokine receptor gene CCR5 showed that homozygous carriers display near-complete resistance to HIV infection, irrespective of exposure. Algorithms of molecular evolutionary theory suggested that the CCR5- ∆ 32 mutation occurred but once in the last millennium and rose by strong selective pressure relatively recently to a ~10% allele frequency in Europeans. Several lines of evidence support the hypothesis that CCR5- ∆ 32 was selected due to its protective influence to resist Yersinia pestis, the agent of the Black Death/bubonic plague of the 14th century. Powerful anti-AIDS entry inhibitors targeting CCR5 were developed as a treatment for HIV patients, particularly those whose systems had developed resistance to powerful anti-retroviral therapies. Homozygous CCR5- ∆ 32/ ∆ 32 stem cell transplant donors were used to produce HIV-cleared AIDS patients in at least five “cures” of HIV infection. CCR5 has also been implicated in regulating infection with Staphylococcus aureus , in recovery from stroke, and in ablation of the fatal graft versus host disease (GVHD) in cancer transplant patients. While homozygous CCR5- ∆ 32/32 carriers block HIV infection, alternatively they display an increased risk for encephalomyelitis and death when infected with the West Nile virus.