Native CGRP Neuropeptide and Its Stable Analogue SAX, But Not CGRP Peptide Fragments, Inhibit Mucosal HIV-1 Transmission

DOI for this manuscript is: 10.3389/fimmu.2021.785072
Published in 2021 by Lucia Lopalco et al.
We tested the capacity of CGRP to inhibit HIV-1 infection in-vivo in humanized mice. We further compared the anti-HIV-1 activities of full-length native CGRP, its metabolically stable analogue SAX, and several CGRP peptide fragments containing its binding C-terminal and activating N-terminal regions. These agonists were evaluated for their capacity to inhibit LCs-mediated HIV-1 trans-infection in-vitro and mucosal HIV-1 transmission in human mucosal tissues ex-vivo.
A single CGRP intravaginal topical treatment of humanized mice, followed by HIV-1 vaginal challenge, transiently restricts the increase in HIV-1 plasma viral loads but maintains long-lasting higher CD4+ T-cell counts. Similarly to CGRP, SAX inhibits LCsmediated HIV-1 trans-infection in-vitro, but with lower potency. This inhibition is mediated via CGRP receptor activation, leading to increased expression of both langerin and STAT4 in LCs. In contrast, several N-terminal and N+C-terminal bivalent CGRP peptide fragments fail to increase langerin and STAT4, and accordingly lack anti-HIV-1 activities. Finally, like CGRP, treatment of human inner foreskin tissue explants with SAX, followed by polarized inoculation with cell-associated HIV-1, completely blocks formation of LC-T-cell conjugates and HIV-1 infection of T-cells. Raw data corresponding to: Kinetics of CD4 and FACS, ex vivo experiments SAX and LCT, FACS for langerin and WB analysis are attached here.

本论文的DOI编号为：10.3389/fimmu.2021.785072，发表于2021年，作者为Lucia Lopalco等人。
本研究旨在验证CGRP在体内抑制HIV-1感染的能力，并在人类化小鼠模型中进行实验。进一步比较了全长原态CGRP、其代谢稳定的类似物SAX以及包含其结合C端和激活N端的几个CGRP肽片段的anti-HIV-1活性。这些激动剂在体外评估了它们抑制LCs介导的HIV-1跨感染的能力，并在体外的人类粘膜组织中评估了粘膜HIV-1传播。
对人类化小鼠进行单次CGRP阴道局部治疗，随后进行HIV-1阴道挑战，暂时限制了HIV-1血浆病毒载量的增加，但维持了长期更高的CD4+ T细胞计数。与CGRP相似，SAX在体外抑制LCs介导的HIV-1跨感染，但效力较低。这种抑制作用通过CGRP受体的激活介导，导致LCs中langerin和STAT4的表达增加。相反，几个N端和N+C端的双价CGRP肽片段未能增加langerin和STAT4的表达，因此缺乏anti-HIV-1活性。最后，与CGRP类似，用SAX处理人类内前臂组织培养物，随后进行极化接种与细胞相关的HIV-1，完全阻止了LC-T细胞共轭的形成和T细胞的HIV-1感染。
附有对应于CD4和FACS、体外实验SAX和LCT、FACS用于langerin和WB分析的原始数据。