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: 6409078
• 负责人: HARRIS GOLDSTEIN
• 金额: $ 35.8万
• 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/6409078
• 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.

高效抗逆转录病毒疗法(HAART)并不能根除体内的HIV-1感染，因为即使经过多年的治疗，携带复制能力病毒的细胞库仍然存在于血液和淋巴组织中。因此，有必要针对潜伏感染的HIV-1感染细胞池开发新的治疗方法。我们建议通过开发一种新的嵌合小鼠模型来促进对这些新治疗方法的评估，该模型中填充了HIV-1感染的小鼠细胞以及对HIV-1感染敏感的人类T细胞。我们已经开发了转基因小鼠，以获得R5嗜性HIV-1JR-CSF的全长前病毒克隆(JR-CSF小鼠)，该小鼠表现为血浆病毒血症，其T细胞、单核细胞和树突状细胞产生传染性HIV-1。这些小鼠的细胞通过与rosa26小鼠杂交来标记，从而产生同时表达HIV-1JR-CSF和β-半乳糖苷酶的转基因小鼠。这些小鼠还与DO11.10 OVA(323-339)-TCR转基因小鼠杂交，允许产生含有复制能力HIV-1的抗原特异性记忆CD4+T细胞。我们现在证明，JR-CSF小鼠细胞被转移到THY/Liv-SCID-Hu小鼠中，作为HIV-1感染细胞的储存库，能够感染人类T细胞和人类胸腺植入物。只要小鼠接受HAART治疗，这种情况就可以预防，但在HAART停止后，即使在HAART治疗1个月后，这种情况也会发生。完全清除能够产生传染性HIV-1的JR-CSF细胞将防止HAART停止后HUTHY/LIV植入物的感染。因此，我们可以通过HAART将Jr-CSF小鼠细胞转移到HAART的THY/LIV-SCID-HU小鼠中，用治疗候选者治疗小鼠，停止HAART治疗，然后评估HIV-1在HAART/LIV植入物中的感染时间，来评估针对持续HIV-1储存库的治疗干预的效果。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有效性，如环境导向毒素和HIV特异性CTL，以耗尽HIV-1感染细胞的数量。我们还将使用我们成熟的THY/LIV-SCID-HU小鼠系统来检验环境导向毒素治疗消除HIV-1感染细胞储存库的有效性。