IMMUNE ACTIVATION AND AIDS PATHOGENESIS IN SIV-INFECTED NON-HUMAN PRIMATES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 与人类感染HIV-1和恒河猴SIV感染与艾滋病相关，自然SIVsmm感染Sooty mangabys(SM)通常是非致病性的。这种非致病表型背后的机制在很大程度上仍不清楚。本项目的目的是了解SIV感染的SMS和RMS在免疫激活方面的差异的分子和细胞基础。为此，我们进行了一项体内实验，用I型干扰素激动剂治疗自然感染SIV的短信。该激动剂是重组人干扰素-α2与免疫球蛋白G-Fc(rh-干扰素-α2-Fc)的融合蛋白。这种rh-干扰素-α2-Fc分子具有生物活性，与重组人干扰素-α2相比，具有更长的体内半衰期和更高的溶解度。在这项研究中，8个自然感染SIV的SM接受了50万单位的干扰素-α2-Fc静脉注射治疗12周。这项研究的主要发现是：(I)干扰素-α2-Fc在SMS体内具有生物活性，并通过基因阵列分析诱导SM细胞强烈的ISG上调，从而表明SM细胞对干扰素的刺激并不具有内在的抵抗力；(Ii)干扰素-α2-Fc可诱导SIV病毒载量对数下降，持续约6周；(Iii)在整个研究过程中，干扰素-α2-Fc不会增加治疗动物的T细胞激活，也不会导致CD4+下降。总体而言，这项实验揭示了外源性I型给药不足以在SIV感染的短信中诱导疾病进展。作为该项目的一部分，目前正在计划对I型干扰素系统在RMS和SMS中的操纵进行进一步研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In contrast to HIV-1 infection of humans and SIV infection of Rhesus macaques (RMs), which are associated with AIDS, natural SIVsmm infection of Sooty mangabeys (SM), is typically non-pathogenic. The mechanisms underlying this non-pathogenic phenotype remain largely unknown. Aim of this project is to understand the molecular and cellular basis for the differences in immune activation in SIV-infected SMs and RMs. To this end, we conducted an in vivo experiment in which naturally SIV-infected SMs are treated with a type I IFN agonist. The agonist is a fusion protein of the RM IFN-alpha2 with the IgG-Fc (rh-IFN-alpha2-Fc). This rh-IFN-alpha2-Fc molecule is bioactive and shows a longer in vivo half-life and higher solubility when compared to rhIFN-alpha2. In this study, eight naturally SIV-infected SMs were treated with 500,000 units of IFN-alpha2-Fc intravenously for twelve weeks. The key findings of this study are: (i) IFN-alpha2-Fc is bioactive in vivo in SMs and induces a strong ISG upregulation as detected by gene array analysis, thus indicating that SM cells are not intrinsically resistant to IFN stimulation; (ii) IFN-alpha2-Fc induces a 1-Log decline in SIV viral load that lasts for ~6 weeks; (iii) IFN-alpha2-Fc does not increase T cell activation, nor CD4+ decline in the treated animals throughout the study. Overall this experiment reveled that exogenous type I administration is not sufficient to induce disease progression in SIV-infected SMs. Further studies of manipulation of the type I IFN system in RMs and SMs are now being planned as part of this project.