ROLE OF NK CELLS IN SIV-INFECTED LONG-TERM NONPROGRESSING RHESUS MACAQUES

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 SIV感染中国恒河猴（Ch Rh）导致三分之一的长期无进展猕猴。我们使用该模型连续研究自然杀伤（NK）细胞在LTNP Ch Rh建立长期非进展状态中的作用，这可以转化为HIV-1感染的疫苗开发。我们发现NK细胞有两个主要亚群：CD 3-CD 8 + CD 16+和CD 3-CD 8 + CD 16-，与人类相似。这两个亚群在外周血和肠粘膜中的分布和功能不同。SIV感染后CD 16+亚群进行性下降。此外，我们还首次发现，在急性感染时，NK细胞上有程序性死亡1（PD-1）的表达。值得注意的是，PD-1表达可能有利于NK细胞的抗病毒功能，这与其在慢性SIV/HIV感染期间对T细胞的负调节（T细胞功能障碍或衰竭）相反。我们还发现NKp 46表达的NK细胞与肠道中细胞因子IL-22的分泌呈正相关，表明该NK细胞亚群可能在SIV或HIV-1感染中提供重要的先天性粘膜免疫防御。总的来说，NK细胞可能比以前想象的要重要得多，特别是它们具有最近发现的新的记忆样“适应性”特征。因此，重新评估NK细胞在HIV/SIV感染中的作用至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SIV infection in rhesus macaques of Chinese origin (Ch Rh) results in one-third of long-term nonprogressing macaques. We used this model for continuous study of the role of natural killer (NK) cells in the establishment of long-term nonprogressing state in LTNP Ch Rh, which could be translated into vaccine development for HIV-1 infection. We found that NK cells have 2 major subsets: CD3-CD8+CD16+ and CD3-CD8+CD16-, similar to that in humans. The distribution and function of these 2 subsets in peripheral blood and in the intestinal mucosa are different. The CD16+ subsets decreased progressively following SIV infection. Furthermore, we found, for the first time, that programmed death 1 (PD-1) expressed on NK cells in acute infection. Remarkably, PD-1 expression may be beneficial to NK cell antiviral functions, which is in contrast to its negative regulation of T cells (T cell dysfunction or exhaustion) during chronic SIV/HIV infection. We also found that NKp46 expressed NK cells had a positive correlation with the secretion of cytokine IL-22 in the gut, indicating that this subset of NK cells may provide important innate mucosal immune defense in SIV or HIV-1 infection. Overall, NK cells are likely much more important than previously thought, particularly they posses new memory-like "adaptive" features that has been discovered recently. Thus, reevaluation of the role of NK cells in HIV/SIV infection is essential.