TOWARDS A MORE RELEVANT MODEL OF HIV INFECTION

建立更相关的 HIV 感染模型

• 批准号: 9526462
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 88万
• 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/9526462
• 关键词: Area; Benchmarking; CD4 Antigens; Cell Culture Techniques; Cells; Chimera organism; Evaluation; Gatekeeping; HIV; HIV Infections; HIV-1; HIV-1 vaccine; Human; Infection; Injecting drug user; Interferons; Intervention; Macaca; Mediating; Methods; Modeling; Pathogenesis; Pathogenicity; 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; public health relevance; 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.

 产品说明：SHIV猕猴模型为临床前HIV-1研究提供了重要的基准，是推进疫苗和其他预防方法的守门人。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人类HIV-1传播和发病机制的关键特征，包括性传播和胃肠外传播。迄今为止，SHIV主要是通过使用最容易获得的HIV-1变体进行试验和错误选择的，通常是那些已经适应在细胞培养中复制的HIV-1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流行变体的关键特征。尽管在这一领域的努力正在增加，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，并向前推进复制最好的嵌合体。值得注意的是，这种产生致病性SHIV的过程包括病毒在猕猴中的连续传代以进一步增加复制适应性，并且目前使用的所有SHIV都以这种方式进行了改造（改造的SHIV）。我们建议开创一种合理的设计方法，以开发相关的SHIV，更好地代表流行的HIV-1变异中心的流行。 我们已经发现了几个障碍，艾滋病毒-1复制猕猴细胞是特定的传播/创始人（T/F）病毒在人类中传播。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是特定于选择HIV-1变体的。 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的复制有显著影响，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屏障是猕猴CD 4受体，它通常是T/F变体的弱受体，但对于实验室适应性变体是功能性受体，这可能解释了基于实验室适应性HIV-1变体开发SHIV的偏好。虽然T/F变异体可以适应猕猴CD 4受体，但适应导致抗原变化，改变了目前HIV-1疫苗工作的核心的几种广泛NAb的识别。在这里，我们建议利用这些初步的研究结果，以确定潜在的机制，在猕猴中的HIV-1复制的病毒介导的限制，定义这些变化的后果模型的效用，并确定开发合理设计的SHIV的途径与增强效用的HIV-1疫苗和预防方法的临床前研究。