PATHOGENESIS OF NEW SIVSMM LINEAGES IN RHESUS MACAQUES

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。 SIVsmm在恒河猴(Rh)体内的内在致病性明显低于人们普遍认为的水平。我们发现，这种新的Rh SIV感染模型的特点是：进展较慢，进展为AIDS；对VLS的控制较强；外周和肠道中的CD4+T细胞逐渐丧失；肠道中的靶细胞部分免疫恢复。我们调查了细胞免疫反应是否与原发SIVsmm分离株感染Rh的致病性较低有关。用3株SIVsmm原代分离株感染22例印度Rh。检测急性和慢性SIVsmm感染时血浆病毒载量(VLS)、体液和细胞免疫反应、血浆细胞因子和趋化因子的动态变化以及免疫表型标志物。在初次感染期间，所有SIVsmm菌株都有高水平的复制。在3个Rh(每组1个)，VL峰值低于10 6个SIVsmm RNA拷贝/ml，慢性感染时设定的VL水平比Rh慢性感染高致病性SIVmac株时低2~4个对数。观察到肠道CD4+T细胞的大量耗尽，并与急性期的病毒复制有关；其大小不能预测慢性感染期间的复制模式。干扰素-γ和IL-2 ELISPOT检测显示，针对4-7个SIV多肽库的SIV特异性细胞免疫反应强烈且定向广泛，与病毒株无关，且与感染SIVmac的Rh的免疫反应大小相同。在慢性SIVsmm感染期间，非洲宿主的T细胞免疫激活水平介于高致病性SIVmac感染和非进行性感染之间。

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 intrinsic pathogenicity of SIVsmm in rhesus macaques (Rh) is significantly lower than widely believed. We showed that this new model of SIV infection in Rh is characterized by: slower progression to AIDS; stronger control of VLs; gradual loss of CD4+ T-cells in both periphery and intestine; partial immune restoration of target cells in the intestine. We investigated whether or not cellular immune responses were responsible for the less pathogenic outcome of Rh infection with primary SIVsmm isolates. Twenty-two Indian Rh were infected with 3 primary SIVsmm isolates. Plasma viral loads (VLs), humoral and cellular immune responses, dynamics of cytokines and chemokines in plasma and immunophenotypic markers were measured during acute and chronic SIVsmm infection. All SIVsmm strains replicated at high levels during primary infection. In 3 Rh (one in each group), peak VLs were lower than 10^6 SIVsmm RNA copies/ml. Set point VL levels during chronic infection were 2-4 log lower than those observed in Rh chronically infected with highly pathogenic SIVmac strains. Massive depletion of intestinal CD4+ T-cells was observed and was related to viral replication during the acute stage; its magnitude was not predictive of replication patterns during the chronic infection. IFN-gamma and IL-2 Elispot assays showed a strong and broadly directed SIV-specific cellular immune response targeting 4-7 SIV peptide pools, independent of the viral strain and of the same order of magnitude as those observed in Rh infected with SIVmac. During chronic SIVsmm infection, the T-cell immune activation levels were intermediate between highly pathogenic SIVmac infections and non-progressive infections in African hosts.