Hunting the HIV-1 Unicorn

项目摘要 虽然已经制定了许多公共卫生策略来降低吸毒者的 HIV-1 感染率，但有效的 HIV-1 疫苗对于这项工作仍然至关重要。尽管这种 HIV-1 感染的灵长类动物模型有许多局限性，但 HIV-1 传播、发病机制和疫苗开发的研究大多在猕猴中进行。自猕猴模型建立以来的几十年里，我们已经了解了大量有关针对 HIV-1 和 SIV 的免疫反应的知识。然而，这种来之不易的知识从未被整合成一种综合的、合理的方法来重新评估 HIV-1 感染的非人类灵长类动物模型。我们提出了一种重新评估不同灵长类物种遗传背景的原则性方法，利用该领域庞大的知识库以及现有的大量遗传多样性。我们将对代表几种关键灵长类物种（恒河猴、猪尾猕猴、猫头鹰猴、狒狒、狨猴和松鼠猴）的数千种非人类灵长类动物的限制因子等位基因进行基因分型，并在基于细胞培养的测定中测试所有发现的针对 HIV-1 的限制因子等位基因。每个发现的等位基因都将被给予 HIV 兼容性评分，从而可以系统、合理地确定哪些物种以及这些物种中的哪些特定个体具有与 HIV-1 最相容的限制因子基因型。作为我们方法的一部分，我们还将评估这些灵长类动物的 MHC、KIR 和抗体受体 (FcR) 基因含量和等位基因多样性。我们将专门测试已发现的针对传播/创始人 (T/F) HIV-1 的等位基因，这是有效疫苗需要识别的变体。我们将测试之前在人类性行为和静脉注射后分离出的 T/F 病毒，这是吸毒者感染 HIV-1 的两种主要方式。最终，我们的研究可能为 HIV-1 发病机制和传播的研究以及药物和疫苗的开发开辟令人兴奋的新途径。

Project Summary While there are many public health strategies in place for reducing HIV-­1 infection rates in drug users, an effective HIV-1 vaccine remains critical to this effort. Studies of HIV-­1 transmission, pathogenesis, and vaccine development are mostly conducted in macaque monkeys, although this primate model of HIV-1 infection has many limitations. In the decades since the macaque model was established, we have learned a tremendous amount about the immune response against HIV­-1 and SIV. However, this hard-earned knowledge has never been synthesized into an integrated, rational approach for re­evaluating the nonhuman primate model for HIV-1 infection. We present a principled approach for re-evaluating the genetic background of different primate species, capitalizing on the enormous knowledge base in the field, and on the substantial genetic diversity that exists. We will genotype restriction factor alleles from thousands of nonhuman primates representing several key primate species (rhesus macaques, pigtailed macaques, owl monkeys, baboons, marmosets, and squirrel monkeys) and test all discovered restriction factor alleles against HIV-1 in cell culture-based assays. Each discovered allele will be given an HIV­-compatibility score, allowing systematic and rational determination of which species, and which specific individuals within those species, have restriction factor genotypes most compatible with HIV­-1. As part of our approach, we will also evaluate MHC, KIR, and antibody receptor (FcR) gene content and allelic diversity in these primate species. We will specifically test discovered alleles against transmitted/founder (T/F) HIV­-1, the variants that an effective vaccine needs to recognize. We will test T/F viruses previously isolated after both sexual and intravenous infection in humans, the two main modes by which drug users acquire HIV-­1 infection. Ultimately, our research could open up exciting new avenues in the study of HIV-­1 pathogenesis and transmission, and in the development of drugs and vaccines.