Legacy of a magic gene-<i>CCR5-<b>∆</b>32</i>: From discovery to clinical benefit in a generation.

Abstract

The discovery of the 32-bp deletion allele of the chemokine receptor gene <i>CCR5</i> showed that homozygous carriers display near-complete resistance to HIV infection, irrespective of exposure. Algorithms of molecular evolutionary theory suggested that the <i>CCR5-<b>∆</b>32</i> 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 <i>CCR5-<b>∆</b>32</i> was selected due to its protective influence to resist <i>Yersinia pestis,</i> 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 <i>CCR5-<b>∆</b>32/<b>∆</b>32</i> 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 <i>Staphylococcus aureus</i>, in recovery from stroke, and in ablation of the fatal graft versus host disease (GVHD) in cancer transplant patients. While homozygous <i>CCR5-<b>∆</b>32/32</i> carriers block HIV infection, alternatively they display an increased risk for encephalomyelitis and death when infected with the West Nile virus.