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.

抗HIV-1广谱中和抗体(BNAbs)领域的最新进展为抗逆转录病毒治疗开辟了道路，并激发了人们对潜在疫苗的希望，无论是预防还是治疗。然而，几个重要的问题仍然不清楚。例如，研究表明，一些感染髓系细胞的原始HIV-1毒株对bNAbs的中和相对耐受，这引发了问题：bNAbs是否允许攻击这个重要的HIV-1储存库，以及初级HIV-1毒株在这些细胞中的持续模式是否与实验室适应毒株不同。我们假设，南美洲循环中的BF重组毒株以及传播型/创立者(T/F)HIV-1毒株有效地存活在髓系细胞中，因此当bNAbs从细胞传播到细胞时，可能会逃避bNAbs的活性。从机制上讲，我们假设HIV-1原代毒株有效地诱导了髓系细胞内部病毒间隔(VCC)，而这些间隔是被bNAbs屏蔽的。此外，我们推测，这种主要的HIV-1毒株操纵CD74-MIF轴是一种提高细胞间传播和病毒传播效率的策略。该项目将揭示主要的HIV-1持续和传播模式，并进一步展望利用相关病毒株评估bNAbs作为相关病毒传播途径的有效抑制剂的前景。

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.