Minocycline Down-Regulates Topical Mucosal Inflammation during the Application of Microbicide Candidates

An effective anti-human immunodeficiency virus-1 (HIV-1) microbicide should exert its action in the absence of causing aberrant activation of topical immunity that will increase the risk of HIV acquisition. In the present study, we demonstrated that the vaginal application of cellulose sulfate (CS) gel induced topical mucosal inflammatory responses; the addition of minocycline to CS gel could significantly attenuate the inflammation in a mice model. The combined gel of CS plus minocycline not only reduced the production of inflammatory cytokines in cervicovaginal lavages (CVLs), also down-regulated the activation of CD4+ T cells and the recruitment of other immune cells including HIV target cells into vaginal tissues. Furthermore, an In vitro HIV-1 pseudovirus infection inhibition assay showed that the combined gel decreased the infection efficacy of different subtypes of HIV-1 pseudoviruses compared with that of CS gel alone. These results implicate that minocycline could be integrated into microbicide formulation to suppress the aberrant activation of topical mucosal immunity and enhance the safety profile during the application of microbicides.一款有效的抗人类免疫缺陷病毒1型（HIV-1）杀微生物剂，应当在发挥抗病毒作用的同时，不会引发局部免疫异常激活——而后者会增加HIV感染风险。本研究证实，硫酸纤维素（CS）凝胶经阴道给药可诱导局部黏膜炎症反应；向CS凝胶中添加米诺环素后，可在小鼠模型中显著减轻此类炎症。CS与米诺环素的复合凝胶不仅能降低宫颈阴道灌洗液（CVLs）中炎性细胞因子的生成，还可下调CD4阳性T细胞的活化水平，并减少包括HIV靶细胞在内的其他免疫细胞向阴道组织的募集。此外，体外HIV-1假病毒感染抑制实验结果显示，与单独使用CS凝胶相比，复合凝胶可降低不同亚型HIV-1假病毒的感染效力。上述结果表明，米诺环素可被整合至杀微生物剂制剂中，以抑制局部黏膜免疫的异常激活，同时提升杀微生物剂使用过程中的安全性。