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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我们最近描述了快速进展（RP）R5 SHIVSF162P3N 感染的恒河猴中的辅助受体转换，这些恒河猴具有高病毒复制，以及不可检测或微弱且短暂的抗病毒抗体反应。缺乏抗体选择性压力，加上观察到新出现的 X4 变体对中和敏感，表明病毒特异性体液免疫反应的缺失或减弱可能是促进体内辅助受体转换的环境因素。为了测试这种可能性，我们从静脉内感染 SHIVSF162P3N 的前一周开始，每 2-3 周用 50 mg/kg 的抗 CD20 抗体利妥昔单抗治疗四只猕猴，总共输注六次。通过流式细胞术和免疫组织化学染色分析，利妥昔单抗治疗成功地耗尽了外周和淋巴 CD20+ 细胞长达 25 周，此后四只接受治疗的猴子中有两只部分恢复到完全恢复。四只接受治疗的猕猴中，三只未能产生可检测到的抗 SHIV 抗体反应，而其余动物的反应则延迟。这三只血清阴性猕猴均罹患疾病，但通过 V3 序列和趋向性分析，均无法证明其中存在 X4 变异。此外，病毒并没有在这些患病猕猴中早期进化为对 sCD4 更加敏感。这些结果表明，体液免疫反应的缺失或减弱本身不足以驱动进化病毒的 R5 至 X4 转换和中和敏感性。