Laher Faatima, Ranasinghe Srinika, Porichis Filippos, Mewalal Nikoshia, Pretorius Karyn, Ismail Nasreen, Buus Søren, Stryhn Anette, Carrington Mary, Walker Bruce D, Ndung'u Thumbi, Ndhlovu Zaza M
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
J Virol. 2017 Mar 13;91(7). doi: 10.1128/JVI.02477-16. Print 2017 Apr 1.
Immune control of viral infections is heavily dependent on helper CD4 T cell function. However, the understanding of the contribution of HIV-specific CD4 T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4 T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4 T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4 T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4 T cells in HIV controllers than progressors ( = 0.0001), and these expanded Gag-specific CD4 T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB11101 was associated with HIV control ( = -0.5, = 0.02). These data identify an association between HIV-specific CD4 T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4 T cell responses in natural infections. Increasing evidence suggests that virus-specific CD4 T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4 T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV infections worldwide. Understanding the contribution of HIV-specific CD4 T cell responses in clade C infection is particularly important for developing vaccines that would be efficacious in sub-Saharan Africa, where clade C infection is dominant. Here, we employed MHC class II tetramers designed to immunodominant Gag epitopes and used them to characterize CD4 T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4 T cell responses targeting an immunodominant DRB111-Gag41 complex and HIV control, highlighting the important contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infections.
病毒感染的免疫控制在很大程度上依赖于辅助性CD4 T细胞的功能。然而，对于HIV特异性CD4 T细胞反应在针对HIV-1的免疫保护中的作用，尤其是在C亚型感染中的作用，目前仍了解不足。最近，主要组织相容性复合体（MHC）II类四聚体已成为一种强大的工具，可用于研究抗原特异性CD4 T细胞，而无需依赖效应器功能。在此，我们确定了C亚型病毒感染中免疫显性Gag CD4 T细胞表位的MHC II类等位基因，构建了MHC II类四聚体，然后用这些四聚体来确定一组未经治疗的HIV C亚型感染者中HIV特异性CD4 T细胞反应的强度、功能及其与病毒载量的关系。我们观察到，HIV控制者中MHC II类四聚体阳性CD4 T细胞的频率显著高于疾病进展者（P = 0.0001），并且这些在HIV控制者中扩增的Gag特异性CD4 T细胞显示出更高水平的细胞溶解蛋白颗粒酶A和B的表达。重要的是，在HLA II类DRB11101背景下靶向免疫显性Gag41肽与HIV控制相关（β = -0.5，P = 0.02）。这些数据确定了HIV特异性CD4 T细胞靶向免疫显性Gag表位与免疫控制之间的关联，特别是单个II类MHC - 肽复合物对针对HIV-1感染的免疫反应的贡献。此外，这些结果突出了使用II类四聚体评估自然感染中HIV特异性CD4 T细胞反应的优势。越来越多的证据表明，病毒特异性CD4 T细胞有助于免疫介导的B亚型HIV-1感染的控制，但关于HIV特异性CD4 T细胞在塑造C亚型感染者适应性免疫反应中的作用的数据仍然相对较少，而C亚型感染在全球大多数HIV感染中占主导地位。了解HIV特异性CD4 T细胞反应在C亚型感染中的作用对于开发在撒哈拉以南非洲有效的疫苗尤为重要，因为在该地区C亚型感染占主导地位。在此，我们采用针对免疫显性Gag表位设计的MHC II类四聚体，并利用它们来表征HIV-1 C亚型感染中的CD4 T细胞反应。我们的结果证明了靶向免疫显性DRB111 - Gag41复合物的HIV特异性CD4 T细胞反应频率与HIV控制之间的关联，突出了单个II类MHC - 肽复合物对针对HIV-1感染的免疫反应做出的重要贡献。
