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.

针对HIV-1的广泛中和抗体（bNAbs）领域的最新进展为抗逆转录病毒治疗开辟了道路，并激发了对潜在疫苗的希望，无论是预防性的还是治疗性的。然而，仍有几个重要问题尚不清楚。例如，研究表明，一些感染髓细胞的原代HIV-1毒株相对难以被bnAbs中和，这就提出了bnAbs是否允许攻击这一重要的HIV-1储存库以及这些细胞中原代HIV-1毒株的持续模式是否与实验室适应毒株不同的问题。我们推测，南美洲原代流行的bf -重组毒株以及传播/创立（T/F） HIV-1毒株在骨髓细胞内有效地持续存在，从而可能在细胞间传播时逃避bNAbs的活性。在机制上，我们假设原代HIV-1毒株有效地诱导髓细胞内部含病毒室（vcc），这些细胞被bNAbs屏蔽。此外，我们假设这种原发HIV-1毒株对CD74-MIF轴的操纵是一种提高细胞间传播和病毒传播效率的策略。该项目将揭示原发HIV-1的持续和传播模式，并进一步为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提供前景。

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.