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

细胞毒性CD8 T细胞(CTL)对HIV病毒具有重要的保护作用。然而，许多研究表明，HIV特异性CD8 T细胞可能在功能上受到损害。此外，我们还证明了HIV特异性CD8T细胞对CD95/Fas介导的细胞凋亡的敏感性增加，HIV感染的巨噬细胞可以杀死这些细胞。因此，HIV特异性CD8 T细胞的这种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细胞的效应器功能和生存能力将极大地提高这些细胞控制或清除HIV病毒的效率。白介素15(IL-15)是一种多能细胞因子，能有效地抑制CD95/Fas介导的HIV特异性CD8T细胞的凋亡，并上调这些细胞中抗凋亡的Bcl2和Bclxl分子。此外，IL-15增强了它们的细胞毒活性和干扰素-γ的产生。SIV感染猕猴的SIV特异性CD8T细胞对CD95/Fas介导的细胞凋亡也表现出更高的敏感性，而IL-15有效地抑制了这种凋亡，并上调了Bcl2和Bclxl分子。基于这些观察，我们最近在慢性SIV感染的食蟹猴身上进行了一项简短的先导性研究，以探讨IL-15治疗在体内的潜在益处。在活体治疗中，IL-15使外周血CD8-T-T细胞和NK细胞数量显著增加2倍以上。这一增加主要是由于CD8T细胞的增殖，随着治疗的进行，增殖的Ki67、CD8T细胞增加。扩增的CD8T细胞具有CD45RA-CD62L-和CD45RA-CD62L-记忆效应表型。我们推测IL-15体内治疗可以增强细胞毒CD8T细胞对SIV的免疫，增强抗病毒免疫。我们建议检测重组猴IL-15体内治疗对恒河猴原发和慢性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。观察病毒载量、免疫学变化、细胞凋亡和Bcl2/Bclxl分子表达情况。特别是，体内IL-15治疗对SIV特异性CTL反应的影响将被研究。这项提案中的研究是新颖的，将为IL-15的潜在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被证明有助于设计针对艾滋病毒感染和其他病毒感染的新的治疗策略。

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.