Influence of HLA-C Expression Level on HIV Control

  • Richard Apps ,
  • Ying Qi ,
  • ,
  • Haoyan Chen ,
  • Xiaojiang Gao ,
  • Rasmi Thomas ,
  • Yuko Yuki ,
  • Greg Q. Del Prete ,
  • Philip Goulder ,
  • Zabrina L. Brumme ,
  • Chanson J. Brumme ,
  • Mina John ,
  • Simon Mallal ,
  • George Nelson ,
  • Ronald Bosch ,
  • ,
  • Judy L. Stein ,
  • Kelly A. Soderberg ,
  • M. Anthony Moody ,
  • Thomas N. Denny ,
  • Xue Zeng ,
  • Jingyuan Fang ,
  • Ashley Moffett ,
  • Jeffrey D. Lifson ,
  • James J. Goedert ,
  • Susan Buchbinder ,
  • Gregory D. Kirk ,
  • Jacques Fellay ,
  • Paul McLaren ,
  • Steven G. Deeks ,
  • Florencia Pereyra ,
  • Bruce Walker ,
  • Nelson L. Michael ,
  • Amy Weintrob ,
  • Steven Wolinsky ,
  • Wilson Liao ,
  • Mary Carrington

Science | , Vol 340(6128): pp. 87-91

论文与出版物

HLA-C expression and HIV immune control

In collaboration with Mary Carrington’s group, we showed in Science that the quantity of HLA-C surface protein correlates with HIV disease progression, the probability than HLA-C epitopes will be targeted by the immune system, and the probability that HIV will escape within those epitopes. Mary further showed that HLA-C expression levels are linked to some auto-immune diseases. This is an important study that highlights the the role of HLA-C (which is generally ignored in the field) and demonstrates how our models of selection can be used to generate and test hypotheses. As always, this was a hugely collaborative effort, making key use of data from Philip Goulder, Zabrina Brumme and many others. The MSR Connections team wrote a blog post providing a nice high-level description.

Abstract

A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn’s disease, suggesting a broader influence of HLA expression levels in human disease.