TOWARDS A MORE RELEVANT MODEL OF HIV INFECTION

 描述：SIV猕猴模型为临床前HIV-1研究提供了一个重要的基准，为先进的疫苗和其他预防方法提供了看门人。这种模型预测干预(S)对人类有效的能力在很大程度上取决于该模型对人类艾滋病毒-1传播和发病机制(包括性传播和肠道外传播)的关键特征的忠实程度。到目前为止，SHIV在很大程度上是通过使用最容易获得的HIV-1变种(通常是那些适应于在细胞培养中复制的变种(实验室适应的HIV-1变种))通过反复试验来选择的。因此，很少有SIV模型包含作为疫苗和其他预防方法靶标的循环变异的关键特征。尽管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变种的SHIV嵌合体，并向前推进复制最好的嵌合体。值得注意的是，这个产生致病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合性，目前使用的所有SHIV都以这种方式进行了适应(适应SHIV)。我们建议开创一种合理的设计方法来开发相关的SHIV，以更好地代表流行中的HIV-1变种。我们已经在猕猴细胞中发现了几个阻止HIV-1复制的障碍，这些障碍是在人类中传播的/创始人(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是特定于选择的HIV-1变种的。 在我们的初步研究中，我们发现，干扰素刺激的反应对编码循环T/F包膜变体的SHIV在猕猴T细胞中的复制有显著影响，但对适应的SHIV没有显著影响。在人类中传播的HIV-1s的另一个关键的物种特异性障碍是猕猴的CD4受体，它通常是T/F变种的一个较差的受体，但对于实验室适应的变种来说是一个功能上的受体，这可能解释了为什么偏向于基于实验室适应的HIV-1变种开发SHIV。虽然T/F变种可以适应使用猕猴的CD4受体，但适应会导致抗原性变化，改变对几种广泛的NAB的识别，这些NAB目前是HIV-1疫苗努力的核心。在这里，我们建议利用这些初步的发现来确定在猕猴中包膜介导的对HIV-1复制的限制的潜在机制，定义这些变化对该模型的实用性的后果，并确定开发合理设计的SHIV的途径，以增强对HIV-1疫苗和预防方法的临床前研究。

 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.