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: 6890916
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890916
• 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）不能从体内根除HIV-1感染，因为即使经过多年的治疗，携带有复制能力的病毒的细胞库仍存在于血液和淋巴组织中。因此，需要开发针对潜伏感染的HIV-1感染细胞库的新治疗方法。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，该模型由HIV-1感染的小鼠细胞以及对HIV-1感染敏感的人T细胞组成。我们已经开发了转基因小鼠的全长前病毒克隆的R5嗜性HIV-1 JR-CSF（JR-CSF小鼠），显示血浆病毒血症，其T细胞，单核细胞和树突状细胞产生感染性HIV-1。通过将这些小鼠的细胞与ROSA 26小鼠杂交来标记它们，以产生表达HIV-1 JR-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，从而产生含有可复制HIV-1的抗原特异性记忆CD 4 + T细胞。我们现在证明，转移到thy/liv-SCID-hu小鼠中的JR-CSF小鼠细胞充当能够感染人T细胞和人胸腺植入物的HIV-1感染细胞的储库。只要用HAART治疗小鼠，就可以防止这种情况，但在HAART停止后，甚至在HAART治疗1个月后，这种情况就会发生。能够产生感染性HIV-1的JR-CSF细胞的完全清除将防止HAART停止后hu-thy/liv植入物的感染。因此，我们可以通过将JR-CSF小鼠细胞转移到进行HAART的thy/liv-SCID-hu小鼠中，用治疗候选物治疗小鼠，停止小鼠的HAART治疗，然后评估hu-thy/liv植入物中HIV-1感染的时间发作，来评估治疗干预针对持续性HIV-1储库的功效。我们将建立模型系统的有效性，并使用它来评估各种治疗的功效，例如Env-定向毒素和HIV-特异性CTL以耗尽HIV-1感染细胞的群体。我们还将使用我们完善的thy/liv-SCID-hu小鼠系统检查Env定向的毒素治疗消除HIV-1感染细胞的储库的功效。