DIFFERENT TGF-BETA PROFILES IN SIVMAC AND SIVAGM INFECTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在非洲绿猴(AGM)的非致病性SIVagm感染中，没有发现人类和猕猴(MACs)感染HIV-1和SIVmac(MACs)的普遍T细胞激活。我们先前已经证明，SIVagm感染后很早就诱导了转化生长因子β1、Foxp3和IL-10的产生。在SIVmac感染的Mac中，血浆转化生长因子β1的诱导在初次感染期间持续存在。我们假设Mac不能对转化生长因子-1做出反应，因此不能控制病毒驱动的炎症。因此，我们比较了SIV感染的巨噬细胞和巨噬细胞中促炎和抗炎分子的早期表达动态，以及参与转化生长因子-1信号转导的因素。在一项包括6个AGM和6个MAC的前瞻性研究中，采用实时定量聚合酶链式反应(Real Time PCR)跟踪了促炎和抗炎分子(TNF-β、干扰素-β、IL-10、T-BET、GATA-3)以及转化生长因子-β1信号介体(SMAD3、Smad4、Smad7)的转录水平。在原发SIVmac感染期间，肿瘤坏死因子-β、干扰素-β和T-BET反应上调(第116天P.I.)IL-10反应延迟(第4周P.I.)与SIVagm感染相比。SIV感染的MACs的特征是SIV感染的Mac上调Smad7(38天P.I.)，Smad7是一种抑制转化生长因子-1信号级联反应的细胞介质。在AGM中，我们发现GATA-3的增加而不是T-BET的增加，Smad4的持续上调(第121天，P.i)，一个促进转化生长因子-β1信号转导的介质，而没有Smad7的上调。 我们的数据表明，无法控制病毒驱动的炎症和激活 在致病过程中，HIV-1/SIVmac感染是由于Smad7的上调抑制了早期的转化生长因子-β的表达。

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. The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-¿1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-¿1 induction persists during primary infection. We hypothesized that MACs are unable to respond to TGF-¿1 and thus cannot control virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory molecules as well as of factors involved in the TGF-¿1 signaling in SIV-infected AGMs and MACs. Levels of transcripts encoding pro- and anti-inflammatory molecules (TNF- ¿, IFN- ¿, IL-10, T-BET, GATA-3) as well as for TGF-¿1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs. During primary SIVmac infection, up-regulations of TNF- ¿, IFN- ¿ and T-BET responses (days 116 p.i.) were stronger whereas IL-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 38 p.i.), a cellular mediator inhibiting the TGF-¿1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of GATA-3 but not T-BET, a longer lasting up-regulation of smad4 (days 121 p.i), a mediator enhancing TGF-¿1 signaling, and no smad7 up-regulations. Our data suggest that the inability to control virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is due to up-regulation of smad7 that inhibits early TGF-beta expression.