Lee Wen Shi, Kristensen Anne B, Rasmussen Thomas A, Tolstrup Martin, Østergaard Lars, Søgaard Ole S, Wines Bruce D, Hogarth P Mark, Reynaldi Arnold, Davenport Miles P, Emery Sean, Amin Janaki, Cooper David A, Kan Virginia L, Fox Julie, Gruell Henning, Parsons Matthew S, Kent Stephen J
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
J Virol. 2017 Jul 12;91(15). doi: 10.1128/JVI.00603-17. Print 2017 Aug 1.
There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells. The "shock and kill" HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined , but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.
利用抗体依赖性细胞毒性（ADCC）来清除从HIV-1潜伏状态重新激活后的感染细胞，正受到越来越多的关注。一个潜在的障碍是，长期接受抗逆转录病毒疗法（ART）的患者体内，HIV-1特异性ADCC抗体水平会下降，可能不足以清除重新激活的潜伏感染细胞。目前尚不清楚使用潜伏逆转剂（LRA）使潜伏状态重新激活是否能提供足够的抗原刺激来增强HIV-1特异性ADCC。我们发现，使用LRA帕比司他治疗或进行21至59天的短期分析性治疗中断（ATI），不足以刺激具有ADCC活性的抗体增加，尽管所有接受短期ATI的受试者都出现了病毒反弹。相比之下，在抗逆转录病毒治疗管理策略（SMART）试验中，为期2至12个月的较长时间的ATI能有力地增强HIV-1 gp120特异性Fc受体结合抗体以及针对HIV-1感染细胞的ADCC。这些结果表明，病毒复发与ADCC抗体增强之间存在滞后现象，这对清除潜伏感染细胞的策略具有重要意义。“激活并清除”HIV-1治愈策略旨在重新激活潜伏感染细胞中的HIV-1表达，随后通过免疫介导的杀伤作用清除重新激活的细胞。已经对几种潜伏逆转剂（LRA）进行了研究，但单独使用LRA未能实现HIV-1缓解，也无法在分析性治疗中断（ATI）后预防病毒反弹。在本研究中，我们研究了LRA治疗或ATI是否能提供足够的抗原刺激来增强可清除HIV-1感染细胞的HIV-1特异性功能性抗体。我们的研究对抗潜伏策略和/或治疗性疫苗增强功能性抗体并协助清除潜伏库所需的抗原刺激具有重要意义。
