Understanding the Role of the Host Response in HIVSIV Infection

途径1：人类免疫缺陷病毒（HIV）感染与免疫激活、CD4(+)- t细胞丢失和免疫功能的进行性下降有关。抗逆转录病毒疗法（ART）只能部分逆转hiv相关的免疫功能障碍，这表明可能需要靶向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）并接受抗逆转录病毒治疗的恒河猴中进行了临床前研究。我们测试了疫苗接种与细胞毒性t淋巴细胞相关抗原4 （CTLA-4）阻断和吲哚胺2,3-双加氧酶（IDO）抑制剂1-甲基-d -色氨酸（D-1mT）治疗是否会降低免疫激活和提高疫苗效力。治疗没有增强疫苗的免疫原性；相反，它极大地增加了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昏迷。暴发性糖尿病的发病与严重的胰腺淋巴细胞浸润和朗格汉斯胰岛的完全丧失有关。因此，在考虑抗逆转录病毒治疗期间靶向免疫激活的方法时应谨慎。方法2：我们之前已经证明，白细胞介素-21是一种多效性C α链信号细胞因子，在体外诱导慢性HIV感染者的CD8 T细胞和NK细胞中细胞毒性分子颗粒酶B （GrB）和穿孔素的表达。在这项初步研究中，4只慢性SIV感染的晚期恒河猴（RM）被静脉注射两剂重组IL-21, 50 mcg/kg，间隔7天，然后在第二次注射后23天皮下注射一次，100 mcg/kg。三只动物作为对照。每次剂量IL-21后，外周血（PB）、外周和肠系膜淋巴结（LN）细胞、PB记忆和效应CD4 T细胞以及NK细胞中CD8 T细胞记忆亚群中GrB和穿孔素表达的频率和平均荧光强度均升高。SIV-gag特异性CD107a(+) ifn - α (+) CD8 T细胞的频率在PB和LN中分别增加3.8倍和1.8倍。此外，IL-21给药后，PB CD27（+）记忆B细胞升高2倍，血清SIV抗体显著升高。在T细胞活化、T细胞增殖或血浆病毒载量的标记物中未观察到变化。因此，给慢性SIV感染的病毒血症动物注射IL-21是安全的，耐受性良好，可以增强T细胞和NK细胞的细胞毒性，促进B细胞分化，增加SIV抗体滴度，而不增加细胞活化。需要进一步的研究来阐明IL-21在SIV/HIV感染和SIV/HIV疫苗设计中的作用和潜在益处。

Approach 1: 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.Approach 2: We have previously shown that interleukin-21, a pleiotropic C alpha-chain signaling cytokine, induces the expression of the cytotoxic molecules granzyme B (GrB) and perforin in vitro in CD8 T cells and NK cells of chronically HIV infected individuals. In this pilot study, four chronically SIV infected rhesus macaques (RM) in late-stage disease were given two doses of recombinant IL-21, 50 mcg/kg, intravenously 7 days apart, followed by one subcutaneous dose, 100 mcg/kg, 23 days after the second dose. Three animals served as controls. After each dose of IL-21, increases were noted in frequency and mean fluorescence intensity of GrB and perforin expression in memory and effector subsets of CD8 T cells in peripheral blood (PB), in peripheral and mesenteric lymph node (LN) cells, in PB memory and effector CD4 T cells and in NK cells. Frequencies of SIV-gag specific CD107a(+)IFN-alpha(+) CD8 T cells increased 3.8-fold in PB and 1.8-fold in LN. In addition, PB CD27(+) memory B cells were 2-fold higher and serum SIV antibodies increased significantly after IL-21 administration. No changes were observed in markers of T cell activation, T cell proliferation or plasma virus load. Thus, administration of IL-21 to chronically SIV infected viremic animals was safe, well tolerated and could augment the cytotoxic potential of T cells and NK cells, promote B cell differentiation with increases in SIV antibody titers without discernable increase in cellular activation. Further studies are warranted to elucidate the effects and potential benefit of IL-21 administration in the context of SIV/HIV infection and in SIV/HIV vaccine design.