PATHOGENESIS OF NEW SIVSMM LINEAGES IN 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来源获得了主要资金， 因此可在其他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。 SIVsmm在恒河猴（Rh）中的内在致病性显著低于普遍认为的。我们发现，这种新的SIV感染模型的特点是：进展缓慢的艾滋病;更强的控制VL; CD 4 + T细胞在外周和肠道逐渐损失;部分免疫恢复的目标细胞在肠道。我们研究了细胞免疫应答是否是Rh感染主要SIVsmm分离株致病性较低的原因。16名印度Rh感染了3个主要SIVsmm分离株。测定了急性和慢性SIVsmm感染时血浆病毒载量（VL）、体液和细胞免疫应答、血浆中细胞因子和趋化因子的动态变化以及免疫表型标志物。所有SIVsmm株在初次感染期间均以高水平复制。在3个Rh（每组1个）中，峰值VL低于10^6 SIVsmm RNA拷贝/ml。慢性感染期间的设定点VL水平比在用高致病性SIVmac毒株慢性感染的Rh中观察到的那些低2- 4log。肠道CD 4 + T细胞的大量消耗被观察到，并与病毒复制在急性期，其幅度是不能预测的复制模式在慢性感染。IFN-γ和IL-2 Elispot测定显示出靶向4-7个SIV肽库的强且广泛定向的SIV特异性细胞免疫应答，其与病毒株无关，并且与在感染SIVmac的Rh中观察到的数量级相同。在慢性SIVsmm感染期间，T细胞免疫活化水平介于非洲宿主中的高致病性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. Sixteen 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.