LSU VETERINARY COBRE: PATHOGENESIS OF NEW SIVSM 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。 我们的假设是，属于不同谱系的SIVsm初级分离株在恒河猴(Rh)中本质上并不像参考菌株那样具有高毒力。用SIVsm原代分离株感染RH可能是HIV-1更好的模式。9个不同的系统发育谱系与HIV-1亚型在灵长类中心共同循环的程度相似。Rh中高致病性SIVmac株的出现与多代连续传代有关。我们的特异性目标(SA)是：SA1：评估属于谱系1(B670的祖先)、谱系8(SIVmac的祖先)和谱系6(先前未在Rh中测试但在SMS中高度中和)的原始SIVsm毒株的体内致病机制，并将它们与高致病原型SIV(SIVsmB670和SIVmac251)进行比较。我们将扩大在一项初步研究中获得的初步结果，以获得具有统计学意义的数据，并确认SIVsm感染确实可以由Rh控制。我们将研究SIVsm感染的免疫发病机制，以及参与控制Rh病毒复制的免疫效应因子(细胞和体液)。将对致病性的病毒决定因素进行调查。SA2：检测CD8 T细胞在控制感染SIVsm原代分离株的Rh病毒复制和疾病进展中的作用。CD8T细胞在控制病原性慢病毒感染中发挥重要作用。我们假设感染SIVsm原始分离株的Rh中的病毒复制是由CD8T细胞控制的。因此，在急性和慢性SIVsm感染期间，我们会耗尽CD8T细胞。SIVsm感染的结果将在耗竭和非耗竭的Rh之间进行比较，以确定是否在血浆和组织VLS、免疫标记物和疾病进展方面存在差异。在SIVsm感染这些低致病性谱系期间的CTL活性将在选定的时间点进行调查。 对这些的研究？祖先？病毒将为控制SIV感染的离散机制提供有价值的见解。不同SIVsm谱系的多样性类似于HIV-1组M亚型的多样性，因此，通过提供大量反映HIV-1多样性的SIVsm毒株，我们将为发病机制和疫苗研究提供一个有用的模型。

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. Our hypothesis is that primary SIVsm isolates belonging to different lineages are not intrinsically as highly virulent in rhesus macaques (Rh) as the reference strains. Rh infection with primary SIVsm isolates may be a better model for HIV-1. Nine different phylogenetic lineages showing similar degrees of divergence as HIV-1 subtypes co-circulate in Primate Centers. Emergence of highly pathogenic SIVmac strains in Rh is related to multiple serial passages. Our specific aims (SA) are: SA1: To assess the in vivo pathogenesis of primary SIVsm strains belonging to lineages 1 (ancestors of B670), lineage 8 (ancestors of SIVmac) and lineage 6 (not previously tested in Rh but highly neutralizable in SMs) and to compare them to the highly pathogenic prototype SIVs (SIVsmB670 and SIVmac251). We will extend the preliminary results obtained during a pilot study to acquire statistically significant data and to confirm that SIVsm infection can indeed be controlled by Rh. We will investigate the immunopathogenesis of SIVsm infection and the immune effectors (cellular and humoral) involved in the control of viral replication in Rh. Viral determinants of pathogenicity will be investigated. SA2: To examine the role of CD8+ T cells in controlling viral replication and disease progression in Rh infected with primary SIVsm isolates. CD8+ T cells play an important role in controlling pathogenic lentiviral infections. We hypothesize that viral replication in Rh infected with primary SIVsm isolates is controlled by CD8+ T cells. Therefore, we will deplete CD8 T cells during acute and chronic SIVsm infection. The outcome of SIVsm infection will be compared between depleted and non-depleted Rh, to determine if differences occur in plasma and tissue VLs, immunologic markers and disease progression. CTL activity during SIVsm infection with these low pathogenic lineages will be investigated on selected time points. The study of these ?ancestral? viruses will offer valuable insights into the discrete mechanisms of control of SIV infection. The diversity of the different SIVsm lineages is similar to that of HIV-1 group M subtypes, therefore by providing a large array of well characterized SIVsm strains mirroring HIV-1 diversity we will provide an useful model for pathogenesis and vaccine studies.