Madhavi Vijaya, Wren Leia H, Center Rob J, Gonelli Christopher, Winnall Wendy R, Parsons Matthew S, Kramski Marit, Kent Stephen J, Stratov Ivan
aDepartment of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville bMelbourne Sexual Health Clinic, Carlton cInfectious Diseases Unit, Alfred Hospital, Prahran, Victoria, Australia.
AIDS. 2014 Aug 24;28(13):1859-70. doi: 10.1097/QAD.0000000000000310.
The objective of this study is to determine the breadth of HIV-1 Env-specific antibody-dependent cellular cytotoxicity (ADCC) in HIV controllers and HIV progressors with a view to design globally relevant HIV vaccines.
The breadth of ADCC towards four major HIV-1 Env subtypes was measured in vitro for 11 HIV controllers and 11 HIV progressors.
Plasma from 11 HIV controllers (including long-term slow progressors, viremic controllers, elite controller and posttreatment controller) and 11 HIV progressors, mostly infected with HIV-1 subtype B, was analysed for ADCC responses. ADCC assays were performed against 10 HIV-1 gp120 and 8 gp140 proteins from four major HIV-1 subtypes (A, B, C and E) and 3 glycosylation-mutant gp140 proteins.
ADCC-mediated natural killer cell activation was significantly broader (P = 0.02) and of higher magnitude (P < 0.001) in HIV controllers than in HIV progressors. HIV controllers also showed significantly higher magnitude of ADCC-mediated killing of Env-coated target cells than HIV progressors to both HIV-1 subtype B and the heterologous subtype E gp140 (P = 0.001). We found good ADCC reactivity to subtype B and E Envs, less cross-reactivity to subtype A and minimal cross-reactivity to subtype C Envs. Glycosylation-dependent ADCC epitopes comprise a significant proportion of the total Env-specific ADCC response, as evident from the reduction in ADCC to nonglycosylated form of HIV-1 gp140 (P = 0.004).
HIV controllers have robust ADCC responses that recognize a broad range of HIV-1 Env. Glycosylation of Env was found to be important for recognition of ADCC epitopes. Identifying conserved ADCC epitopes will assist in designing globally relevant ADCC-based HIV vaccines.
本研究的目的是确定HIV控制者和HIV进展者中HIV-1 Env特异性抗体依赖性细胞毒性（ADCC）的广度，以期设计出全球适用的HIV疫苗。
对11名HIV控制者和11名HIV进展者体外测量针对四种主要HIV-1 Env亚型的ADCC广度。
分析了11名HIV控制者（包括长期缓慢进展者、病毒血症控制者、精英控制者和治疗后控制者）和11名主要感染HIV-1 B亚型的HIV进展者的血浆ADCC反应。针对来自四种主要HIV-1亚型（A、B、C和E）的10种HIV-1 gp120和8种gp140蛋白以及3种糖基化突变型gp140蛋白进行ADCC检测。
与HIV进展者相比，HIV控制者中ADCC介导的自然杀伤细胞激活明显更广泛（P = 0.02）且强度更高（P < 0.001）。HIV控制者对HIV-1 B亚型和异源E亚型gp140的Env包被靶细胞的ADCC介导杀伤强度也明显高于HIV进展者（P = 0.001）。我们发现对B亚型和E亚型Env有良好的ADCC反应性，对A亚型交叉反应性较低，对C亚型交叉反应性极小。糖基化依赖性ADCC表位占总Env特异性ADCC反应的很大比例，这从对HIV-1 gp140非糖基化形式的ADCC降低中可以明显看出（P = 0.004）。
HIV控制者具有强大的ADCC反应，可识别多种HIV-1 Env。发现Env的糖基化对于ADCC表位的识别很重要。鉴定保守的ADCC表位将有助于设计全球适用的基于ADCC的HIV疫苗。
