IL-15 treatment of SIV-infected non-human primates

细胞毒性CD8+ T细胞（CTL）反应对HIV病毒起关键的保护作用。然而，许多研究表明，hiv特异性CD8+ T细胞可能功能受损。此外，我们已经证明hiv特异性CD8+ T细胞对CD95/ fas介导的凋亡表现出更高的敏感性，并且hiv感染的巨噬细胞可以杀死这些细胞。因此，这种hiv特异性CD8+ T细胞的凋亡可能会削弱它们作为连环杀手的能力。增强HIV特异性CD8+ T细胞的效应功能和存活将大大提高这些细胞控制或清除HIV病毒的效率。白细胞介素15 （IL-15）是一种多能细胞因子，我们已经证明它能有效抑制CD95/ fas介导的hiv特异性CD8+ T细胞的凋亡，并上调这些细胞中抗凋亡的Bcl-2和Bcl-xL分子。此外，IL-15增强了它们的细胞毒活性和IFNgamma的产生。来自siv感染恒河猴的siv特异性CD8+ T细胞对CD95/ fas介导的凋亡也表现出更高的敏感性，IL-15能有效抑制这种凋亡并上调Bcl-2和Bcl-xL分子。基于这些观察结果，我们最近在慢性siv感染的食蟹猕猴中进行了一项简短的初步研究，以研究IL-15治疗在体内的潜在有益作用。在体内用IL-15处理后，外周血CD8-t细胞和NK细胞数量明显增加2倍以上。这种增加主要是由于CD8+ T细胞的增殖，因为Ki67^ CD8+ T细胞的增殖随着治疗而增加。扩增的CD8+ T细胞为CD45RA- CD62L-和CD45RA+ CD62L-效应记忆表型。我们假设IL-15在体内治疗可以增强细胞毒性CD8+ T细胞对SIV的免疫，并增强抗病毒免疫。我们拟研究重组猴IL-15在体内对恒河猴原发性和慢性SIV感染的影响。与抗逆转录病毒治疗的协同作用也将在慢性感染研究中进行评估。评估病毒载量、免疫变化、细胞凋亡和Bcl-2/Bcl-xL分子表达。特别是体内IL-15治疗对siv特异性CTL反应的影响将被研究。本研究是新颖的，将为IL-15潜在的治疗价值提供有价值的信息。从这些研究中获得的信息可能对设计针对HIV感染和其他病毒感染的新治疗策略有用。

Cytotoxic CD8+ T cell (CTL) responses play a critical protective role against HIV virus. A number of studies, however, have indicated that HIV-specific CD8+ T cells may be functionally impaired. Furthermore, we have demonstrated that HIV-specific CD8+ T cells exhibit increased susceptibility to undergo CD95/Fas-mediated apoptosis and HIV-infected macrophages can kill these cells. This apoptosis of HIV-specific CD8+ T cells therefore may impair their ability to function as serial killers. Augmenting the effector function and the survival of HIV-specific CD8+ T cells would greatly enhance the efficiency of these cells to control or clear HIV virus. Interleukin 15 (IL-15) is a pluripotent cytokine that we have shown potently inhibits CD95/Fas-mediated apoptosis of HIV-specific CD8+ T cells and upregulates the anti-apoptotic Bcl-2 and Bcl-xL molecules in these cells. Furthermore IL-15 enhances their cytotoxic activity and IFNgamma production. SIV-specific CD8+ T cells from SIV-infected rhesus macaques also show increased sensitivity to CD95/Fas-mediated apoptosis and IL-15 potently inhibits this apoptosis and upregulates Bcl-2 and Bcl-xL molecules. Based on these observations, we recently performed a short pilot study in chronically SIV-infected cynomolgus macaques to investigate the potentially beneficial effect of IL-15 treatment in vivo. In vivo treatment with IL-15 significantly increased peripheral blood CD8-t- T cell and NK cell numbers by more than 2-fold. This increase was mainly due to proliferation of CD8+ T cells, as proliferating Ki67^ CD8+ T cells increased with treatment. The expanded CD8+ T cells were of the CD45RA- CD62L- and CD45RA+ CD62L- effector memory phenotype. We hypothesize that IL-15 treatment in vivo can enhance cytotoxic CD8+ T cells immunity against SIV and enhance antiviral immunity. We propose to examine the effect of in vivo treatment with recombinant simian IL-15 on primary and chronic SIV infection of rhesus macaques. Synergy with ART treatment will also be evaluated in chronic infection studies. Viral load, immunological changes, apoptosis and Bcl-2/Bcl-xL molecule expression will be evaluated. In particular the effect of in vivo IL-15 treatment on SIV-specific CTL response will be investigated. The studies in this proposal are novel and will provide valuable information on the potential therapeutic value of IL-15. Information yielded from these studies may prove useful for the design of novel therapeutic strategies against HIV infection and other viral infections.