TOWARDS A MORE RELEVANT MODEL OF HIV INFECTION

建立更相关的 HIV 感染模型

• 批准号: 9144750
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 87.12万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144750
• 关键词: Area; Benchmarking; CD4 Antigens; Cell Culture Techniques; Cells; Chimera organism; Evaluation; Gatekeeping; HIV; HIV Infections; HIV-1; HIV-1 vaccine; Health; Human; Infection; Injecting drug user; Interferons; Intervention; Macaca; Mediating; Methods; Modeling; Pathogenesis; Pathway interactions; Pre-Clinical Model; Prevention; Prevention approach; Process; Research; Serial Passage; Series; T-Lymphocyte; Testing; Vaccines; Variant; Virus; base; design; fitness; pandemic disease; pre-clinical; preclinical study; receptor; response; simian human immunodeficiency virus; transmission process

 DESCRIPTION: SHIV macaque models provide an important benchmark for pre-clinical HIV-1 research, serving as a gatekeeper for advancing vaccine and other prevention approaches. The ability of such models to predict intervention(s) that will be efficacious in humans depends to a large extent on how faithfully the model recapitulates key features of HIV-1 transmission and pathogenesis in humans, including both sexual and parenteral transmission. To date, SHIVs have largely been selected by trial and error using the most readily available HIV-1 variants, often those that have been adapted to replication in cell culture (lab-adapted HIV-1 variants). As a result, few SHIV models incorporate key features of circulating variants that are the target of vaccine and other prevention methods. Although efforts in this area are increasing, approaches nonetheless generally rely on constructing and testing a series of SHIV chimeras encoding available HIV-1 variants and moving forward the one that replicates best. Of note, this process of generating pathogenic SHIVs includes serial passage of the virus in macaques to further increase replication fitness, and all of the SHIVs in current use have been adapted in this manner (adapted SHIVs). We propose to pioneer a rational design approach to developing relevant SHIVs that better represent circulating HIV-1 variants central to the pandemic. We have found several barriers to HIV-1 replication in macaque cells that are specific to transmitted/founder (T/F) viruses circulating in humans. These restrictions do not appear to be the result of known restriction factors, which are generally not specific to select HIV-1 variants. In our preliminary studies, we found that IFN-stimulated responses have a pronounced effect on the replication of SHIVs encoding circulating T/F envelope variants in macaque T cells, but not on adapted SHIVs. Another critical species-specific barrier of HIV-1s circulating in humans is the macaque CD4 receptor, which is generally a poor receptor for T/F variants, but a functional receptor for lab-adapted variants, potentially explaining the bias towards developing SHIVs based on lab-adapted HIV-1 variants. While T/F variants can be adapted to use the macaque CD4 receptor, adaptation leads to antigenic changes that alter recognition of several broad NAbs that are currently the centerpiece of HIV-1 vaccine efforts. Here, we propose to exploit these preliminary findings to define the mechanisms underlying the envelope-mediated restrictions to HIV-1 replication in macaques, to define the consequences of these changes for the utility of the model and to identify pathways to developing rationally designed SHIVs with enhanced utility for preclinical studies of HIV-1 vaccine and prevention methods.

 描述：SHIV 猕猴模型为临床前 HIV-1 研究提供了重要基准，充当推进疫苗和其他预防方法的把关人。此类模型预测对人类有效的干预措施的能力在很大程度上取决于该模型如何忠实地概括 HIV-1 传播和人类发病机制的关键特征，包括性传播和肠外传播。迄今为止，SHIV 很大程度上是通过使用最容易获得的 HIV-1 变体进行试验和错误来选择的，通常是那些已经适应在细胞培养中复制的变体（实验室适应的 HIV-1 变体）。因此，很少有 SHIV 模型包含作为疫苗和其他预防方法目标的循环变异的关键特征。尽管这一领域的努力不断增加，但方法通常依赖于构建和测试一系列编码可用 HIV-1 变体的 SHIV 嵌合体，并向前推进复制效果最好的嵌合体。值得注意的是，产生致病性 SHIV 的过程包括病毒在猕猴中的连续传代，以进一步提高复制适应性，并且当前使用的所有 SHIV 都已以这种方式进行了改造（适应的 SHIV）。我们建议开创一种合理的设计方法来开发相关的 SHIV，以更好地代表对大流行至关重要的流行的 HIV-1 变异。 我们发现了猕猴细胞中 HIV-1 复制的几个障碍，这些障碍是人类传播的传播/创始 (T/F) 病毒所特有的。这些限制似乎不是已知限制因素的结果，这些限制因素通常不特定于特定的 HIV-1 变体。 在我们的初步研究中，我们发现 IFN 刺激的反应对猕猴 T 细胞中编码循环 T/F 包膜变体的 SHIV 的复制有显着影响，但对适应的 SHIV 没有影响。 HIV-1 在人类中传播的另一个关键的物种特异性障碍是猕猴 CD4 受体，它通常对 T/F 变体来说是一种较差的受体，但却是实验室适应的变体的功能性受体，这可能解释了基于实验室适应的 HIV-1 变体开发 SHIV 的偏见。虽然 T/F 变体可以适应使用猕猴 CD4 受体，但适应会导致抗原变化，从而改变对几种广泛 NAb 的识别，而这些 NAb 是目前 HIV-1 疫苗工作的核心。在这里，我们建议利用这些初步发现来定义猕猴中包膜介导的 HIV-1 复制限制机制，定义这些变化对模型效用的影响，并确定开发合理设计的 SHIV 的途径，增强 HIV-1 疫苗和预防方法临床前研究的效用。