TRANSMISSION & PATHOGENESIS OF X4 & R5 SHIVS

传播

• 批准号: 8172933
• 负责人: CECILIA C CHENG-MAYER
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172933
• 关键词: Address; Anatomic Sites; Animals; Antibody Formation; CD4 Positive T Lymphocytes; Cell Count; Computer Retrieval of Information on Scientific Projects Database; Drops; Event; Evolution; Funding; Grant; HIV Envelope Protein gp120; HIV-1; Human; Infection; Institution; Kinetics; Macaca; Macaca mulatta; Modeling; Pathogenesis; Pathway interactions; Pattern; Peripheral; Reporting; Research; Research Personnel; Resources; Site; Source; Tissues; United States National Institutes of Health; V3 Loop; Viral Antibodies; Virus; Virus Replication; base; env Gene Products; lymph nodes; preference; simian human immunodeficiency virus; transmission process

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. We previously reported coreceptor switch in rhesus macaques inoculated intravenously with R5 simian-human immunodeficiency virus SF162P3N (SHIV(SF162P3N)). Whether R5-to-X4 virus evolution occurs in mucosally infected animals and in which anatomic site the switch occurs, however, were not addressed. We herein report a change in coreceptor preference in macaques infected intrarectally with SHIV(SF162P3N). The switch occurred in infected animals with high levels of virus replication and undetectable antiviral antibody response and required sequence changes in the V3 loop of the gp120 envelope protein. X4 virus emergence was associated with an accelerated drop in peripheral CD4(+) T-cell count but followed rather than preceded the onset of CD4(+) T-cell loss. The conditions, genotypic requirements, and patterns of coreceptor switch in intrarectally infected animals were thus remarkably consistent with those found in macaques infected intravenously. They also overlapped with those reported for humans, suggestive of a common mechanism for coreceptor switch in the two hosts. Furthermore, two independent R5-to-X4 evolutionary pathways were identified in one infected animal, giving rise to dual-tropic and X4 viruses which differed in switch kinetics and tissue localization. The dual-tropic switch event predominated early, and the virus established infection in multiple tissues sites. In contrast, the switch to X4 virus occurred later, initiating and expanding mainly in peripheral lymph nodes. These findings help define R5 SHIV(SF162P3N) infection of rhesus macaques as a model to study the mechanistic basis, dynamics, and sites of HIV-1 coreceptor switch.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们之前报道了静脉注射 R5 猿-人类免疫缺陷病毒 SF162P3N (SHIV(SF162P3N)) 的恒河猴中的辅助受体转换。然而，R5 病毒向 X4 病毒的进化是否发生在粘膜感染的动物中，以及这种转变发生在哪个解剖部位，尚未得到解决。我们在此报告了直肠内感染 SHIV (SF162P3N) 的猕猴辅助受体偏好的变化。这种转变发生在感染动物身上，这些动物具有高水平的病毒复制和不可检测的抗病毒抗体反应，并且需要 gp120 包膜蛋白 V3 环的序列变化。 X4病毒的出现与外周CD4(+) T细胞计数的加速下降有关，但X4病毒的出现是在CD4(+) T细胞丧失开始之后而不是之前发生的。因此，直肠内感染动物的条件、基因型要求和辅助受体转换模式与静脉内感染的猕猴中发现的情况非常一致。它们也与人类报道的结果重叠，表明两个宿主中存在共同受体转换的机制。此外，在一只受感染的动物中发现了两条独立的 R5-to-X4 进化途径，产生了双热带病毒和 X4 病毒，它们的转换动力学和组织定位不同。双向转换事件在早期占主导地位，病毒在多个组织部位建立了感染。相比之下，向 X4 病毒的转变发生得较晚，主要在外周淋巴结中启动和扩展。这些发现有助于将恒河猴的 R5 SHIV(SF162P3N) 感染定义为研究 HIV-1 辅助受体转换的机制基础、动力学和位点的模型。