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

这个子项目是许多研究子项目中的一个 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来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 中国恒河猴（Ch Rh）中SIV感染导致高频率（30%）的长期非进展性猕猴，其发病率明显高于HIV-1感染的人或印度源SIV感染的猕猴（5%）。我们使用这种独特的模型来研究自然杀伤细胞在LTNP Ch Rh建立长期非进展状态中的作用，这可以为疫苗设计提供直接的影响/指导，以对抗HIV-1感染。这些LTNP动物的高峰病毒血症与进展性Ch Rh或Ind Rh难以区分，表明这不是由于固有的病毒耐药性，而更可能是免疫应答负责病毒复制的最终控制。到目前为止，我们发现中和抗体和T细胞免疫应答都与长期非进展无明显相关性。有趣的是，在天然免疫和NK细胞应答的研究中，我们发现在急性SIV感染期间，NK细胞在LTNP和NP之间具有不同水平的周转; NK细胞通过细胞毒性和不同NK亚群释放抗病毒细胞因子的机制成为强效杀伤细胞。我们还发现，高SIV特异性的非NAb反应引起，这可能与NK细胞介导的抗体依赖性细胞介导的细胞毒性（ADCC）。我们的数据表明，NK细胞可能在预防疾病方面发挥重要作用。通过操纵NK细胞和功能来抵抗感染，新一代疫苗的开发可能是合理的，以控制在长期非进展状态下的感染，这将延长无艾滋病生存期，并可能减少病毒在人群水平上的传播。

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 high frequency (30%) of long-term nonprogressing macaques which is a markedly larger incidence than can be found in HIV-1 infected humans or SIV-infected macaques of Indian origin ( 5%). We use this unique model for investigating the role of natural killer cells in the establishment of long-term nonprogressing state in LTNP Ch Rh, which could provide direct implications/guidance for vaccine design to combat HIV-1 infection. These LTNP animals have high peak viremia indistinguishable from progressing Ch Rh or Ind Rh, indicating that this is not due to inherent viral resistance, but more likely, that immune responses are responsible for the ultimate control of viral replication. Thus far, we found that neither neutralizing antibodies nor T-cell immune responses are clearly correlated with long-term nonprogression. Interestingly, in the study of innate immunity and NK cell responses, we found that NK cells had different levels of turnover between LTNP and NP during acute SIV infection; NK cells were potent killers through mechanisms of both cytotoxicity and release of antiviral cytokines by different NK subsets. We also found that high SIV-specific non-NAb responses were elicited, which may be related to NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Our data demonstrate that NK cells may play an important role in protection from disease. By manipulating NK cells and function to resist infection, new generation of vaccine development may be plausible for controlling infection under an aviremic long term nonprogressive state which will prolong AIDS-free survival and will possibly reduce viral transmission in a population level.