在粘膜传播时,HIV1型(HIV-1)快速靶向生殖器抗原呈递朗格汉斯细胞(LCs),随后将感染性病毒转移到CD4+T细胞。我们之前描述了一种抑制性神经免疫串扰,其中降钙素基因相关肽(CGRP),一种神经肽,由外周疼痛感知伤害性感受器神经元分泌,支配所有粘膜上皮并与LCs相关,强烈抑制HIV-1转移。由于伤害感受器在激活其Ca2离子通道瞬时受体电位香草素1(TRPV1)后秘密CGRP,正如我们报道的那样,LCs隐藏着低水平的CGRP,我们调查了LCs是否表达功能性TRPV1。我们发现人LCs表达TRPV1的mRNA和蛋白,在TRPV1激动剂激活后具有功能性和诱导Ca2+流入,包括辣椒素(CP)。用TRPV1激动剂治疗LC也增加CGRP分泌,达到其抗HIV-1抑制浓度。因此,CP预处理显著抑制LC介导的HIV-1向CD4+T细胞的转移,已被TRPV1和CGRP受体拮抗剂废除。像CGRP,CP诱导的HIV-1转移抑制是通过增加CCL3分泌和HIV-1降解介导的。CP还抑制直接CD4+T细胞HIV-1感染,而是以CGRP独立的方式。最后,用CP预处理内包皮组织外植体显著增加CGRP和CCL3分泌,并且在随后极化暴露于HIV-1后,抑制了LC-T细胞缀合物形成的增加,从而抑制了T细胞感染。我们的结果表明,人LC和CD4+T细胞中的TRPV1激活抑制粘膜HIV-1感染,通过CGRP依赖/独立机制。含有TRPV1激动剂的制剂,已经批准缓解疼痛,因此可能对HIV-1有用。
Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ T cells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ T cells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ T cells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-T cell conjugate formation and consequently T cell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ T cells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.