Persistence of primary patient-derived HIV-1 strains in myeloid cells and modes of virus transmission to T cells: Susceptibility to bNAbs and role of MIF/CD74 axis.

原发性患者来源的 HIV-1 毒株在骨髓细胞中的持久性以及病毒传播至 T 细胞的模式：对 bNAb 的敏感性以及 MIF/CD74 轴的作用。

• 批准号: 431861552
• 负责人: Professor Dr. Michael Schindler
• 金额: --
• 依托单位: Consejo Nacional de Investigaciones Científicas y Técnicas
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/431861552?language=en
• 关键词: Persistence; primary; patient; derived; HIV

The recent developments in the field of broadly neutralizing antibodies (bNAbs) against HIV-1 open avenues for antiretroviral therapy and inspire hope for a potential vaccine, either prophylactic or therapeutic. However, several important issues remain unclear. For instance, it has been shown that some primary HIV-1 strains infecting myeloid cells are relative refractory against neutralization by bnAbs, raising the question whether bNAbs allow attacking this important HIV-1 reservoir and whether modes of primary HIV-1 strain persistence in these cells differ from that of lab-adapted strains.We hypothesize that primary in South America circulating BF-recombinant strains, as well as transmitted/founder (T/F) HIV-1 strains efficiently persist within myeloid cells and might thereby escape from the activity of bNAbs when transmitted from cell-to-cell. Mechanistically, we postulate that primary HIV-1 strains efficiently induce myeloid-cell internal virus-containing-compartments (VCCs) that are shielded from access by bNAbs. Furthermore, we postulate that manipulation of the CD74-MIF axis by this primary HIV-1 strains is a strategy to enhance the efficiency of cell-to-cell transmission and viral spread. This project will reveal modes of primary HIV-1 persistence and transmission and furthermore give prospects to evaluate bNAbs as potent inhibitors of pertinent viral transmission routes using relevant viral strains.

抗HIV-1的广泛中和抗体（bNAb）领域的最新进展为抗逆转录病毒治疗开辟了道路，并激发了对潜在疫苗的希望，无论是预防性的还是治疗性的。然而，若干重要问题仍不清楚。例如，已经表明，一些感染骨髓细胞的原代HIV-1毒株对bnAb的中和相对难治，这提出了bNAb是否允许攻击这一重要的HIV-1储库以及原代HIV-1毒株在这些细胞中持续存在的模式是否与实验室适应的毒株不同的问题。以及传播/创始者（T/F）HIV-1毒株有效地持续存在于骨髓细胞内，从而当从细胞到细胞传播时可能逃避bNAb的活性。从机制上讲，我们假设，主要的HIV-1菌株有效地诱导骨髓细胞内部的病毒含有隔间（VCC），从访问屏蔽bNAbs。此外，我们推测，操纵的CD 74-MIF轴的主要HIV-1株是一种策略，以提高细胞间的传输和病毒传播的效率。该项目将揭示原发性HIV-1持续存在和传播的模式，并进一步提供使用相关病毒株评估bNAb作为相关病毒传播途径的有效抑制剂的前景。