Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Amgen Inc., Thousand Oaks, California, USA.
JCI Insight. 2017 Apr 6;2(7):e88533. doi: 10.1172/jci.insight.88533.
HIV vaginal transmission accounts for the majority of newly acquired heterosexual infections. However, the mechanism by which HIV spreads from the initial site of viral entry at the mucosal surface of the female genital tract to establish a systemic infection of lymphoid and peripheral tissues is not known. Once the virus exits the mucosa it rapidly spreads to all tissues, leading to CD4 T cell depletion and the establishment of a viral reservoir that cannot be eliminated with current treatments. Understanding the molecular and cellular requirements for viral dissemination from the genital tract is therefore of great importance, as it could reveal new strategies to lengthen the window of opportunity to target the virus at its entry site in the mucosa where it is the most vulnerable and thus prevent systemic infection. Using HIV vaginal infection of humanized mice as a model of heterosexual transmission, we demonstrate that blocking the ability of leukocytes to respond to chemoattractants prevented HIV from leaving the female genital tract. Furthermore, blocking lymphocyte egress from lymph nodes prevented viremia and infection of the gut. Leukocyte trafficking therefore plays a major role in viral dissemination, and targeting the chemoattractant molecules involved can prevent the establishment of a systemic infection.
HIV 通过阴道传播占新发异性传播感染的大多数。然而，HIV 从女性生殖道黏膜表面最初的病毒进入部位传播到建立淋巴和外周组织的系统性感染的机制尚不清楚。一旦病毒离开黏膜，它会迅速传播到所有组织，导致 CD4 T 细胞耗竭，并建立一个目前治疗方法无法消除的病毒储存库。因此，了解病毒从生殖道传播的分子和细胞要求非常重要，因为这可能揭示新的策略，以延长在黏膜的病毒进入部位靶向病毒的机会窗口，因为这是最脆弱的部位，从而防止系统性感染。我们使用人源化小鼠的 HIV 阴道感染作为异性传播的模型，证明了阻断白细胞对趋化因子的反应能力可阻止 HIV 离开女性生殖道。此外，阻止淋巴细胞从淋巴结迁出可防止病毒血症和肠道感染。因此，白细胞迁移在病毒传播中起着重要作用，靶向相关趋化因子分子可以防止建立系统性感染。
