PDF(Pubmed)
Abstract：
Previous studies on highly HIV-1-exposed, yet persistently seronegative women from the Punwami Sex Worker cohort in Kenya, have shed light on putative protective mechanisms, suggesting that mucosal immunological factors, such as antiproteases, could be mediating resistance to HIV-1 transmission in the female reproductive tract. Nine protease inhibitors were selected for this study: serpin B4, serpin A1, serpin A3, serpin C1, cystatin A, cystatin B, serpin B13, serpin B1 and α-2-macroglobulin-like-protein 1. We assessed in a pilot study, the activity of these antiproteases with cellular assays and an ex vivo HIV-1 challenge model of human ecto-cervical tissue explants. Preliminary findings with both models, cellular and tissue explants, established an order of inhibitory potency for the mucosal proteins as candidates for pre-exposure prophylaxis when mimicking pre-coital use. Combination of all antiproteases considered in this study was more active than any of the individual mucosal proteins. Furthermore, the migration of cells out of ecto-cervical explants was blocked indicating potential prevention of viral dissemination following amplification of the founder population. These findings constitute the base for further development of these mucosal protease inhibitors for prevention strategies.
摘要：
先前对高度暴露于HIV-1的研究，然而，来自肯尼亚Punwami性工作者队列的持续血清阴性妇女，阐明了推定的保护机制，这表明粘膜免疫因素，如抗蛋白酶，可能是介导女性生殖道对HIV-1传播的抵抗。本研究选择了9种蛋白酶抑制剂：serpinB4，serpinA1，serpinA3，serpinC1，胱抑素A，胱抑素B,serpinB13，serpinB1和α-2-巨球蛋白样蛋白1。我们在一项试点研究中评估，这些抗蛋白酶的活性与细胞测定和人宫颈外植体的离体HIV-1攻击模型。两种模型的初步发现，细胞和组织外植体，在模拟性交前使用时，建立了粘膜蛋白作为暴露前预防候选物的抑制效力顺序。本研究中考虑的所有抗蛋白酶的组合比任何单独的粘膜蛋白都更具活性。此外，细胞从宫颈外植体的迁移被阻断,这表明在建立者群体扩增后可能预防病毒的传播.这些发现构成了进一步开发用于预防策略的这些粘膜蛋白酶抑制剂的基础。
