Transgenic/SCID-hu Mouse Model to Study HIV Therapeutics

用于研究 HIV 治疗的转基因/SCID-hu 小鼠模型

• 批准号: 6632432
• 负责人: HARRIS GOLDSTEIN
• 金额: $ 37.58万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632432
• 关键词: AIDS therapy; HIV envelope protein; HIV infections; SCID mouse; antiAIDS agent; antibody specificity; antiviral agents; cell population study; combination therapy; cyclins; cytotoxic T lymphocyte; cytotoxicity; disease /disorder model; drug screening /evaluation; genetically modified animals; helper T lymphocyte; human immunodeficiency virus 1; human tissue; immunoconjugates; immunotoxicity; latent virus infection; model design /development; nonhuman therapy evaluation

Highly active antiretroviral therapy (HAART) does not eradicate HIV-1 infection from the body because reservoirs of cells harboring replication- competent virus persist in blood and lymphoid tissue even after years of treatment. Thus, there is a need to develop new therapeutic approaches targeting the pool of latently infected HIV-1-infected cells. We propose to facilitate evaluation of these new treatments by developing a new chimeric mouse model populated with HIV-1-infectious mouse cells as well as human T cells susceptible to HIV-1 infection. We have developed mice transgenic for a full-length proviral clone of R5-tropic HIV-1JR-CSF (JR-CSF mice) that displays plasma viremia and whose T cells, monocytes and dendritic cells produce infectious HIV-1. Cells from these mice have been tagged by crossing them with ROSA26 mice to yield mice transgenic for both the expression of HIV-1JR-CSF and beta-galactosidase. These mice have also been crossed with DO11.10 OVA (323-339)-TCR transgenic mice permitting generation of antigen-- specific memory CD4+ T cells containing replication-competent HIV-1. We now demonstrate that JR-CSF mouse cells transferred into thy/liv- SCID-hu mice function as a reservoir of HIV-1-infected cells capable of infecting the human T cells and human thymic implant. This is prevented as long as the mice were treated with HAART, but occurs after HAART is stopped, even after 1 month of HAART. Complete clearance of the JR-CSF cells capable of producing infectious HIV-1 would prevent infection of the hu-thy/liv implant after HAART was stopped. Thus, we could evaluate the efficacy of therapeutic interventions to target persistent HIV-1 reservoirs by transferring JR-CSF mouse cells into thy/liv-SCID-hu mice on HAART, treating the mice with the therapeutic candidates, stopping HAART treatment of the mice, and then evaluating the temporal onset of HIV-1 infection in the hu-thy/liv implant. We will establish the validity of the model system and use it to evaluate the efficacy of various treatments such as Env-directed toxins, and HIV- specific CTL to deplete the population of HIV-1-infected cells. We will also examine the efficacy of Env-directed toxin-treatment to eliminate reservoirs of HIV-1-infected cells using our well-established thy/liv- SCID-hu mouse system.

高度活跃的抗逆转录病毒疗法（HAART）不会消除体内的HIV-1感染，因为即使经过多年的治疗，具有复制性病毒的细胞仍然存在于血液和淋巴组织中。因此，有必要开发针对潜在感染的HIV-1感染细胞池的新治疗方法。我们建议通过开发一种由HIV-1感染小鼠细胞以及容易受到HIV-1感染的人类T细胞的新嵌合小鼠模型来促进对这些新处理的评估。我们已经开发了R5-循环的HIV-1JR-CSF（JR-CSF小鼠）的全长病毒性克隆的小鼠转基因，该克隆显示出血浆病毒血症，其T细胞，单核细胞和树突状细胞会产生感染性HIV-1。这些小鼠的细胞已通过将它们与Rosa26小鼠交叉，以产生HIV-1JR-CSF和β-半乳糖苷酶表达的小鼠转基因。这些小鼠也已与DO11.10 OVA（323-339）-TCR转基因小鼠交叉，允许生成抗原 - 特定的记忆CD4+ T细胞，其中含有复制功能能力的HIV-1。现在，我们证明，JR-CSF小鼠细胞转移到您的/liv-scid-hu小鼠中充当能够感染人类T细胞和人类胸腺植入物的HIV-1感染细胞的储层。只要用HAART处理小鼠，就可以避免这种情况，但即使在HAART 1个月后，也会发生在Haart停止之后。完全清除能够产生感染性HIV-1的JR-CSF细胞，将阻止HAART停止后的Hu-thy/Liv植入物感染。因此，我们可以通过将JR-CSF小鼠细胞转移到HAART上的您的/liv-SCID-HU小鼠中，以HAART治疗小鼠，并使用HAART治疗HAART对HAART治疗，然后在Huiv-1 Intection中评估HAART治疗，从而评估HAART的小鼠，并评估HAART治疗HAART的治疗方法，从而评估HAART的小鼠，并评估HAART的临时iniv-1 Intement iniv-1 Intemant，我们可以评估治疗干预措施对靶标HIV-1储存剂的疗效。我们将建立模型系统的有效性，并使用它来评估各种治疗方法的功效，例如ENV指导的毒素和HIV-特异性CTL以耗尽HIV-1感染的细胞群体。我们还将使用我们已建立的您/liv-scid-hu小鼠系统来检查ENV指导的毒素治疗消除HIV-1感染细胞储层的功效。