R5 SHIV/MACAQUE MODEL FOR THE EVALUATION OF T AND B CELL-BASED HIV-1 VACCINE

用于评估基于 T 细胞和 B 细胞的 HIV-1 疫苗的 R5 SHIV/猕猴模型

• 批准号: 8358132
• 负责人: CECILIA C CHENG-MAYER
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358132
• 关键词: Animals; Antibodies; Antibody Formation; B-Lymphocytes; Cells; Disease; Environmental Risk Factor; Evaluation; Flow Cytometry; Fostering; Funding; Grant; HIV-1; Immune response; Infection; Infusion procedures; Intravenous; Lymphoid; MS4A1 gene; Macaca; Macaca mulatta; Modeling; Monkeys; National Center for Research Resources; Peripheral; Predisposition; Primates; Principal Investigator; Recovery; Research; Research Infrastructure; Resources; Source; Staining method; Stains; T-Lymphocyte; Testing; Tropism; United States National Institutes of Health; Vaccines; Variant; Viral Antibodies; Virus; Virus Replication; base; cost; in vivo; pressure; response; rituximab; simian human immunodeficiency virus; tositumomab

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. We recently described coreceptor switch in rapid progressor (RP) R5 SHIVSF162P3N-infected rhesus macaques that had high virus replication, and undetectable or weak and transient antiviral antibody response. The lack of antibody selective pressure, together with the observation that the emerging X4 variants were neutralization sensitive, suggested that the absence or weakening of virus-specific humoral immune response could be an environmental factor fostering coreceptor switching in vivo. To test this possibility, we treated four macaques with 50 mg/kg of the anti-CD20 antibody rituximab every 2-3 weeks starting from the week prior to intravenous infection with SHIVSF162P3N for a total of six infusions. Rituximab treatment successfully depleted peripheral and lymphoid CD20+ cells for up to 25 weeks when analyzed by flow cytometry and immunohistochemical staining, with partial to full recovery in two of the four treated monkeys thereafter. Three of the four treated macaques failed to mount a detectable anti-SHIV antibody response while response was delayed in the remaining animal. The three seronegative macaques progressed to disease, but in none of them could be demonstrated the presence of X4 variants by V3 sequence and tropism analyses. Furthermore, viruses did not evolve early in these diseased macaques to be more sCD4-sensitive. These results demonstrate that the absence or diminution of humoral immune responses by itself is insufficient to drive R5-to-X4 switch and neutralization susceptibility of the evolving viruses.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 我们最近描述了快速进度者（RP）R5 SHIVSF162P3N感染的恒河猕猴中的Coreceptor Switch，该猕猴具有很高的病毒复制，并且无法检测到或弱且弱和短暂的抗病毒抗体反应。缺乏抗体选择压力，以及新兴X4变体具有中和敏感的观察，表明病毒特异性的体液免疫反应的缺失或弱化可能是促进体内共感受器切换的环境因素。为了测试这种可能性，我们用50 mg/kg的抗CD20抗体利妥昔单抗治疗了四个猕猴，从静脉内感染前一周开始使用SHIVSF162P3N的一周开始，每2-3周总共输注了6次。当通过流式细胞仪和免疫组织化学染色分析时，利妥昔单抗处理成功耗尽了外周和淋巴CD20+细胞25周，此后的四个处理过的猴子中有两只都可以完全恢复。四个处理过的猕猴中的三个未能安装可检测的抗湿抗体反应，而剩余动物的反应延迟了。这三个血清念珠猕猴发展成为疾病，但通过V3序列和tropism分析，无法证明X4变体的存在。此外，在这些患病的猕猴中，病毒并没有发展为更敏感。这些结果表明，体液免疫反应本身的缺失或减少不足以驱动R5至X4转换和不断发展的病毒的中和敏感性。