Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
Nat Med. 2013 Jul;19(7):930-3. doi: 10.1038/nm.3229. Epub 2013 Jun 23.
The contribution of HLA class II-restricted CD4(+) T cell responses to HIV immune control is poorly defined. Here, we delineated previously uncharacterized peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors. We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with HLA-DRB115:02 significantly associated with low viremia and HLA-DRB103:01 significantly associated with high viremia. Notably, a subgroup of HLA-DRB1 variants linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 variants linked with high viremia. Our data provide systematic evidence that HLA-DRB1 variant expression has a considerable impact on the control of HIV replication, an effect that seems to be mediated primarily by the protein specificity of CD4(+) T cell responses to HIV Gag and Nef.
HLA Ⅱ类限制性 CD4(+) T 细胞应答对 HIV 免疫控制的贡献尚未明确。本研究通过功能性检测，鉴定了 HLA-DRB1 等位基因对 HIV 病毒载量的影响，发现了之前未被描述的与 DRB1 肽结合的限制，研究了在大量 HIV 感染者和进展者中，HLA-DRB1 等位基因对 HIV 病毒载量的遗传效应。结果发现，HLA-DRB1 等位基因对 HIV 病毒载量的影响存在明显的分层，HLA-DRB115:02 与低病毒载量显著相关，HLA-DRB103:01 与高病毒载量显著相关。值得注意的是，与低病毒载量相关的 HLA-DRB1 变异体能够与更多种类的 HIV gag 和 nef 肽结合，且结合亲和力较低，而与高病毒载量相关的 HLA-DRB1 变异体则不能。本研究提供了系统的证据，表明 HLA-DRB1 变体的表达对 HIV 复制的控制有显著影响，这种影响似乎主要是由 CD4(+) T 细胞对 HIV gag 和 nef 的蛋白特异性反应介导的。
