Shete Ashwini, Thakar Madhuri, Singh Dharmesh P, Gangakhedkar Raman, Gaikwad Asmita, Pawar Jyoti, Paranjape Ramesh
National AIDS Research Institute, Pune, India.
AIDS Res Hum Retroviruses. 2012 Aug;28(8):835-43. doi: 10.1089/aid.2010.0363. Epub 2011 Nov 21.
Therapeutic vaccinations using human immunodeficiency virus (HIV) antigens in HIV-infected patients on antiretroviral therapy (ART) have so far been attempted with the purpose of inducing CTL response. However, they can also be useful as a strategy for activation of latent HIV reservoir, which is thought to be mainly comprised of latently infected HIV-specific memory CD4 cells, eventually leading to elimination of the virus. The present study was carried out to explore the ability of different HIV antigens to activate HIV replication as assessed by intracellular P24 detection as well as to induce T cell responses in terms of cytokine expression by flow cytometry after stimulation of PBMCs from HIV-infected patients. HIV antigens were found to be able to activate most of the CD4 T cells harboring proviral DNA. HIV-1 Pol and Env were responsible for induction of higher HIV replication in terms of both magnitude and frequency followed by Gag and Nef. As opposed to this, Pol and Env contributed to fewer numbers of polyfunctional CD8 cells desirable for elimination of HIV-infected cells in comparison to Gag and Nef. Thus, HIV antigens may provide a strategy for the activation of a latent reservoir. It was observed that HIV replication started as early as half an hour after in vitro activation indicating a stringent need for maintaining effective concentrations of antiretroviral drugs to prevent further spread of HIV during this process. HIV-infected cells were found to be responsible for higher IL-10 secretion after activation, which could also serve as one of the reasons for suppressed CD8 responses to Pol and Env as more HIV-infected CD4 cells would be secreting IL-10 in response to these antigens. Since IL-10 blockade helped to improve immune responses in terms of cytokine secretion, it should be considered in settings of therapeutic vaccination to improve CTL responses, which will ultimately limit the persistence of the viral reservoir.
在接受抗逆转录病毒疗法（ART）的HIV感染患者中，使用人类免疫缺陷病毒（HIV）抗原进行治疗性疫苗接种，迄今为止都是以诱导细胞毒性T淋巴细胞（CTL）反应为目的。然而，它们也可作为激活潜伏HIV储存库的一种策略，据认为该储存库主要由潜伏感染的HIV特异性记忆CD4细胞组成，最终导致病毒的清除。本研究旨在探索不同HIV抗原激活HIV复制的能力（通过细胞内P２４检测进行评估），以及在刺激HIV感染患者的外周血单核细胞（PBMC）后，通过流式细胞术检测细胞因子表达来诱导T细胞反应。发现HIV抗原能够激活大多数携带前病毒DNA的CD4 T细胞。就激活的幅度和频率而言，HIV-1聚合酶（Pol）和包膜糖蛋白（Env）诱导的HIV复制水平更高，其次是核衣壳蛋白（Gag）和负调控因子（Nef）。与此相反，与Gag和Nef相比，Pol和Env诱导产生的多功能CD8细胞数量较少，而这些细胞对于清除HIV感染细胞是必不可少的。因此，HIV抗原可能为激活潜伏储存库提供一种策略。据观察，HIV复制在体外激活后半小时就开始了，这表明在此过程中迫切需要维持抗逆转录病毒药物的有效浓度，以防止HIV进一步传播。发现HIV感染细胞在激活后会分泌更高水平的白细胞介素-10（IL-10），这也可能是CD8细胞对Pol和Env反应受到抑制的原因之一，因为更多的HIV感染CD4细胞会针对这些抗原分泌IL-10。由于阻断IL-10有助于改善细胞因子分泌方面的免疫反应，因此在治疗性疫苗接种的情况下应考虑使用，以改善CTL反应，这最终将限制病毒储存库的持续存在。
