Madhavi Vijaya, Kulkarni Archana, Shete Ashwini, Lee Wen S, Mclean Milla R, Kristensen Anne B, Ghate Manisha, Wines Bruce D, Hogarth Phillip M, Parsons Matthew S, Kelleher Anthony, Cooper David A, Amin Janaki, Emery Sean, Thakar Madhuri, Kent Stephen J
*Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia; †Department of Immunology and Serology, National AIDS Research Institute, Pune, India; ‡Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia; §Department of Immunology, Monash University Central Clinical School, Melbourne, Victoria, Australia; ‖Department of Pathology, the University of Melbourne, Melbourne, Victoria, Australia; ¶Kirby Institute, University of New South Wales, Sydney, Australia; #St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Australia; **Melbourne Sexual Health Clinic and Infectious Diseases Department, Alfred Hospital, Central Clinical School, Monash University, Carlton, Victoria, Australia; and ††ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, the University of Melbourne, Melbourne, Australia.
J Acquir Immune Defic Syndr. 2017 Jul 1;75(3):345-353. doi: 10.1097/QAI.0000000000001380.
There is growing interest in immune therapies to clear the latent HIV-1 after combination antiretroviral therapy (cART). There is limited information on the effect of cART on antibody-dependent cellular cytotoxicity (ADCC), and no studies have directly compared ADCC in HIV-1 subtype B- and subtype C-infected subjects. The effect of improving immunocompetence on ADCC to influenza also remains unexplored.
The effect of cART on HIV-1- and influenza-specific ADCC was analyzed in 2 cohorts (39 subtype B- and 47 subtype C-infected subjects) before and after 2 years of cART. ADCC analyses included an enzyme-linked immunosorbent assay-based dimeric recombinant soluble (rs) FcγRIIIa-binding assay, antibody-dependent natural killer cell activation assay, and ADCC-mediated killing assays.
HIV-1 subtype B and C Env-specific antibody binding to dimeric rsFcγRIIIa were reduced in subtypes B- and C-infected cohorts after 2 years of cART (both P < 0.05). Reduced ADCC-mediated killing of target cells expressing subtype B Env in the subtype B-infected cohort (P = 0.003) was observed after 96 weeks of cART, but not of subtype C Env in the subtype C-infected cohort. A greater reduction in ADCC was detected in subjects with baseline CD4 counts >300 cells/μL (P < 0.05). The resolving immunodeficiency after 96 weeks of cART resulted in improved HA-specific ADCC to 6 strains of influenza (all P < 0.01).
cART results in HIV-1 antigen loss and reductions in HIV-1 Env-specific antibodies with Fc functionality in both subtype B- and C-infected subjects, particularly in immunocompetent subjects. Simultaneously, cART improves ADCC to diverse strains of influenza, suggesting reduction in influenza disease after cART.
在接受联合抗逆转录病毒疗法（cART）后，采用免疫疗法清除潜伏的HIV-1引起了越来越多的关注。关于cART对抗体依赖性细胞毒性（ADCC）的影响，相关信息有限，且尚无研究直接比较HIV-1 B亚型和C亚型感染者的ADCC情况。改善免疫能力对流感ADCC的影响也尚未得到探索。
在2个队列（39例B亚型感染者和47例C亚型感染者）中，分析了cART治疗2年前后对HIV-1特异性和流感特异性ADCC的影响。ADCC分析包括基于酶联免疫吸附测定的二聚体重组可溶性（rs）FcγRIIIa结合测定、抗体依赖性自然杀伤细胞激活测定以及ADCC介导的杀伤测定。
在接受cART治疗2年后，B亚型和C亚型感染者队列中，HIV-1 B亚型和C亚型Env特异性抗体与二聚体rsFcγRIIIa的结合减少（均P < 0.05）。在B亚型感染者队列中，cART治疗96周后，观察到ADCC介导的对表达B亚型Env的靶细胞的杀伤减少（P = 0.003），但在C亚型感染者队列中，对表达C亚型Env的靶细胞的杀伤未减少。在基线CD4计数>300个细胞/μL的受试者中，检测到ADCC的更大程度降低（P < 0.05）。cART治疗96周后免疫缺陷的改善导致对6株流感病毒的HA特异性ADCC增强（均P < 0.01）。
cART导致HIV-1抗原丢失，且在B亚型和C亚型感染者中，尤其是免疫功能正常的受试者中，具有Fc功能的HIV-1 Env特异性抗体减少。同时，cART增强了对多种流感病毒株的ADCC，提示cART后流感疾病减少。
