Legacy of a magic gene-CCR5-Δ32: From discovery to clinical benefit in a generation

• 成果类型: Article
• 署名作者: Obrien, Stephen J.
• 署名单位: Nova Southeastern University; Indiana University System; Indiana University Bloomington
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12834
• DOI: 10.1073/pnas.2321907121
• 发表日期: 2024-03-19
• 关键词: retroviruses htlv-iii; immunodeficiency-virus type-1; chemokine receptor ccr5; hiv-1 infection; resistance; aids; ccr5-delta-32; progression; RISK; gene

摘要

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-Delta 32 mutation occurred but once in the last millennium and rose by strong selective pressure relatively recently to a similar to 10% allele frequency in Europeans. Several lines of evidence support the hypothesis that CCR5-Delta 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-Delta 32/Delta 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-Delta 32/ 32 carriers block HIV infection, alternatively they display an increased risk for encephalomyelitis and death when infected with the West Nile virus.