Animal Models & Retroviral Vaccines Section, NCI, NIH, Bethesda, Maryland, USA.
J Virol. 2012 Jan;86(1):108-13. doi: 10.1128/JVI.05609-11. Epub 2011 Oct 19.
Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4⁺-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIV(mac251) and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.
人类免疫缺陷病毒(HIV)感染与免疫激活、CD4+T 细胞损失以及免疫功能的进行性下降有关。抗逆转录病毒疗法(ART)仅部分逆转与 HIV 相关的免疫功能障碍,这表明可能需要针对免疫激活和改善病毒特异性免疫反应的方法。我们在感染致病性猴免疫缺陷病毒 SIV(mac251)并接受 ART 治疗的恒河猴中进行了一项临床前研究。我们测试了与细胞毒性 T 淋巴细胞相关抗原 4(CTLA-4)阻断一起接种疫苗和使用吲哚胺 2,3-双加氧酶(IDO)抑制剂 1-甲基-D-色氨酸(D-1mT)治疗是否可以降低免疫激活并提高疫苗效力。该治疗并未增强疫苗的免疫原性;相反,它极大地增加了与 ART 相关的毒性,导致所有接受治疗的动物都死于急性胰腺炎和高血糖性昏迷。暴发性糖尿病的发作与胰腺的严重淋巴细胞浸润和胰岛的完全丧失有关。因此,在考虑针对 ART 期间的免疫激活的方法时应谨慎。