Hunting the HIV-1 Unicorn

狩猎 HIV-1 独角兽

• 批准号: 10343694
• 负责人: Sara Sawyer
• 金额: $ 92.4万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343694
• 关键词: Alleles; Biological Assay; Callithrix; Cell Culture Techniques; Drug user; Fc Receptor; Genes; Genetic; Genetic Variation; Genotype; HIV; HIV-1; HIV-1 vaccine; Human; Immune response; Individual; Infection; Intravenous; Knowledge; Macaca; Macaca mulatta; Macaca nemestrina; Modeling; Monkeys; Needles; Night Monkey; Papio; Pathogenesis; Primates; Public Health; Research; SIV; Saimiri; T-Cell Receptor; Testing; Vaccines; Variant; Virus; base; drug development; infection rate; killer inhibitory receptor; knowledge base; nonhuman primate; transmission process; vaccine development

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.

项目摘要虽然有许多公共卫生策略可以降低吸毒者的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。 HIV-1传播，发病机理和疫苗发育的研究主要是在猕猴中进行的，尽管这种HIV-1感染的私人模型具有许多局限性。在建立猕猴模型以来的几十年中，我们已经了解了针对HIV-1和SIV的免疫响应的巨大数量。但是，这种艰难的知识从未被合成为一种综合的，合理的方法来重新评估HIV-1感染的非人类私人模型。我们提出了一种重新评估不同灵长类动物的遗传背景的主要方法，利用了该领域的巨大知识基础以及存在的实质遗传多样性。我们将来自代表几个关键主要物种的数千个非人类灵长类动物的基因型限制因子等位基因（猕猴，尾巴猕猴，猫头鹰猴，狒狒，猴子和松鼠猴子），并测试所有在基于细胞培养的分析中针对HIV-1的限制因子等位基因。每个发现的等位基因将获得艾滋病毒兼容的评分，允许对哪种物种以及这些物种中哪些特定个体具有限制性因子基因型的基因型最兼容。作为方法的一部分，我们还将评估这些主要物种中MHC，KIR和抗体受体（FCR）基因含量和等位基因多样性。我们将针对传输/创始人（T/F）HIV-1（有效疫苗需要识别的变体）进行特殊测试发现的等位基因。我们将测试人类性和静脉内感染后先前分离出的T/F病毒，这是吸毒者获得HIV-1感染的两种主要模式。最终，我们的研究可以在HIV-1发病机理和传播以及药物和疫苗的开发中开辟令人兴奋的新途径。

项目成果

Saliva TwoStep for rapid detection of asymptomatic SARS-CoV-2 carriers.

• DOI: 10.7554/elife.65113
• 发表时间: 2021-03-29
• 期刊: eLife
• 影响因子: 7.7
• 作者: Yang Q;Meyerson NR;Clark SK;Paige CL;Fattor WT;Gilchrist AR;Barbachano-Guerrero A;Healy BG;Worden-Sapper ER;Wu SS;Muhlrad D;Decker CJ;Saldi TK;Lasda E;Gonzales P;Fink MR;Tat KL;Hager CR;Davis JC;Ozeroff CD;Brisson GR;McQueen MB;Leinwand LA;Parker R;Sawyer SL
• 通讯作者: Sawyer SL

How avian influenza viruses spill over to mammals.

• DOI: 10.7554/elife.86051
• 发表时间: 2023-04-11
• 期刊: eLife
• 影响因子: 7.7
• 作者: Barbachano-Guerrero A;Perez DR;Sawyer SL
• 通讯作者: Sawyer SL

Just 2% of SARS-CoV-2-positive individuals carry 90% of the virus circulating in communities.

• DOI: 10.1073/pnas.2104547118
• 发表时间: 2021-05-25
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Yang Q;Saldi TK;Gonzales PK;Lasda E;Decker CJ;Tat KL;Fink MR;Hager CR;Davis JC;Ozeroff CD;Muhlrad D;Clark SK;Fattor WT;Meyerson NR;Paige CL;Gilchrist AR;Barbachano-Guerrero A;Worden-Sapper ER;Wu SS;Brisson GR;McQueen MB;Dowell RD;Leinwand L;Parker R;Sawyer SL
• 通讯作者: Sawyer SL