LSU VETERINARY COBRE: PATHOGENESIS OF NEW SIVSM LINEAGES IN RHESUS MACAQUES

路易斯安那州立大学兽医 COBRE：恒河猴新 SIVSM 谱系的发病机制

• 批准号: 7960591
• 负责人: CRISTIAN APETREI
• 金额: $ 4.97万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960591
• 关键词: Acute; CD8B1 gene; Centers of Research Excellence; Chronic; Computer Retrieval of Information on Scientific Projects Database; Data; Disease Progression; Funding; Grant; HIV-1; Immune; Immunologic Markers; Infection; Infectious Diseases Research; Institution; Macaca mulatta; Modeling; Outcome; Pathogenesis; Pathogenicity; Phylogenetic Analysis; Pilot Projects; Plasma; Play; Primates; Research; Research Personnel; Resources; Role; SIV; Serial Passage; Source; T-Lymphocyte; Testing; Time; Tissues; United States National Institutes of Health; Vaccines; Viral; Virulent; Virus; in vivo; insight; prototype

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.

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， 因此可以在其他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。 我们的假设是，属于不同谱系的主要SIVsm分离株在恒河猴（Rh）中的毒性并不像参考株那样高。Rh感染的主要SIVsm分离株可能是一个更好的模型HIV-1。九个不同的系统发育谱系显示出类似程度的分歧，艾滋病毒-1亚型共同循环在灵长类中心。Rh中高致病性SIVmac株的出现与多次连续传代有关。我们的具体目标（SA）是：SA 1：评估属于谱系1（B670的祖先）、谱系8（SIVmac的祖先）和谱系6（以前未在Rh中检测，但在SM中高度中和）的原发性SIVsm毒株的体内发病机制，并将其与高致病性原型SIV（SIVsmB 670和SIVmac 251）进行比较。我们将扩展在试点研究中获得的初步结果，以获得统计学上有意义的数据，并确认SIVsm感染确实可以控制Rh。我们将研究SIVsm感染的免疫发病机制和参与Rh病毒复制控制的免疫效应物（细胞和体液）。将研究致病性的病毒决定因素。SA 2：检测CD 8 + T细胞在控制原发性SIVsm分离株感染Rh的病毒复制和疾病进展中的作用。CD 8 + T细胞在控制致病性慢病毒感染中发挥重要作用。我们假设，在Rh感染的主要SIVsm分离株的病毒复制是由CD 8 + T细胞控制。因此，我们将在急性和慢性SIVsm感染期间耗尽CD 8 T细胞。将在耗竭和非耗竭Rh之间比较SIVsm感染的结果，以确定血浆和组织VL、免疫学标志物和疾病进展是否存在差异。将在选定的时间点研究SIVsm感染这些低致病性谱系期间的CTL活性。 这些研究？祖先的？病毒将提供有价值的见解离散机制的控制SIV感染。不同SIVsm谱系的多样性与HIV-1 M组亚型的多样性相似，因此通过提供大量反映HIV-1多样性的良好表征的SIVsm毒株，我们将为发病机制和疫苗研究提供有用的模型。