Pathogenic determinants of the SIV envelope transmembrane cytoplasmic domain

SIV包膜跨膜胞质结构域的致病决定因素

• 批准号: 8847629
• 负责人: James A Hoxie
• 金额: $ 79.52万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847629
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Anatomy; Animals; Antibodies; Award; B-Lymphocytes; Biochemical; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chronic; Cytoplasmic Tail; Defect; Disease; Distal; Employee Strikes; Event; Exhibits; Future; Genetic; HIV Infections; HIV-1; Human; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Infection Control; Laboratories; Link; Lymphoid Tissue; Macaca nemestrina; Mediating; Modeling; Monitor; Mutation; Pathogenesis; Pathogenicity; Peripheral; Phenotype; RNA; Research; SIV; Serum; Shapes; Signal Transduction; Structure; T memory cell; T-Lymphocyte; Translating; Vaccine Research; Vaccines; Viral; Virion; Virus; Virus Assembly; Virus Diseases; adaptive immunity; cytokine; enzyme linked immunospot assay; fitness; immune activation; in vivo; insight; model development; mutant; nonhuman primate; novel; prevent; regenerative; research study; simian human immunodeficiency virus; trafficking

DESCRIPTION (provided by applicant): Critical research gaps remain in understanding 1) the link between HIV infection and disease; 2) host determinants for viral control; and 3) what immune responses are needed to protect individuals from HIV infection and/or disease. Non-human primate (NHP) models have been invaluable in developing paradigms for HIV-1 infection in humans and vaccine research that can inform human trials. However, NHP models are still needed that can reliably and robustly address viral/host determinants and mechanisms that underlie host control and protection from infection. During the 3 year award of AI074362, our laboratory has validated a powerful and novel NHP model to study host control of SIVmac in pigtail macaques (PTMs), a NHP species now recognized as being highly susceptible to SIV-induced disease. We have shown that when SIVmac239, which reproducibly causes AIDS in PTMs, contains a mutation that ablates a GYxxO trafficking signal in the Env TM cytoplasmic tail, the resulting virus, termed ?GY, replicates to a high acute RNA peak comparable to that of SIVmac239, but with the onset of host immune responses is suppressed to undetectable levels. These animals exhibit only a mild and transient reduction in CD4/CCR5 T-cells in gut lymphoid tissue and maintain normal numbers of peripheral CD4 T-cells for months to years. Importantly, ?GY-infected PTMs have been protected from homologous SIVmac239 challenges and able to control an i.v. infection of a pathogenic heterologous SIV (E660) suggesting that immune responses that can control ?GY are also effective against genetically diverse, pathogenic SIVs. In vitro ?GY virions contain less Env and become highly neutralization sensitive indicating that basic mechanisms at the cellular level, which underlie this novel in vivo phenotype, can be explored. Four aims are proposed to further extend the development of this model: Aim #1 will evaluate host determinants that are required for this elite control in ?GY-infected PTMs; Aim #2 will define host immune responses in ?GY-infected controllers that are relevant to protection and/or control of challenges with SIVmac239 and pathogenic, heterologous SIVs; Aim #3 will develop the unique ability of the ?GY model to explore underlying mechanisms by performing a comprehensive assessment of virologic, structural, genetic, and biochemical alterations in Env that are induced by the ?GY mutation; Aim #4 will extend the ?GY model of host control and protection to a pathogenic SHIV, where immune correlates of protection and control can be assessed in the context of an HIV-1 Env. In contrast to other NHP/SIV models, this PTM/?GY model provides a unique opportunity to link events at the viral/cellular interface to critical determinants of pathogenesis and to identify immune correlates that are relevant to control and protection.

描述（由申请人提供）：关键的研究差距仍然存在于理解1)艾滋病毒感染和疾病之间的联系；2)控制病毒的宿主决定因素；3)需要什么样的免疫反应来保护个人免受艾滋病毒感染和/或疾病。非人类灵长类动物（NHP）模型在开发人类HIV-1感染的范例和可为人体试验提供信息的疫苗研究方面具有宝贵的价值。然而，NHP模型仍然需要能够可靠和健壮地处理病毒/宿主决定因素和宿主控制和保护感染的机制。

项目成果

The SIV Envelope Glycoprotein, Viral Tropism, and Pathogenesis: Novel Insights from Nonhuman Primate Models of AIDS.

SIV 包膜糖蛋白、病毒趋向性和发病机制：来自非人类灵长类艾滋病模型的新见解。

• DOI: 10.2174/1570162x15666171124123116
• 发表时间: 2018
• 期刊: Current HIV research
• 影响因子: 1
• 作者: Swanstrom,AdrienneE;DelPrete,GregoryQ;Deleage,Claire;Elser,SamraE;Lackner,AndrewA;Hoxie,JamesA
• 通讯作者: Hoxie,JamesA