Guzzo Christina, Ichikawa David, Park Chung, Phillips Damilola, Liu Qingbo, Zhang Peng, Kwon Alice, Miao Huiyi, Lu Jacky, Rehm Catherine, Arthos James, Cicala Claudia, Cohen Myron S, Fauci Anthony S, Kehrl John H, Lusso Paolo
Viral Pathogenesis Section, Laboratory of Immunoregulation (LIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
B-Cell Molecular Immunology Section, LIR, NIAID, NIH, Bethesda, MD 20892, USA.
Sci Immunol. 2017 May 12;2(11). doi: 10.1126/sciimmunol.aam7341.
The intestinal mucosa is a key anatomical site for HIV-1 replication and CD4 T cell depletion. Accordingly, in vivo treatment with an antibody to the gut-homing integrin α4β7 was shown to reduce viral transmission, delay disease progression, and induce persistent virus control in macaques challenged with simian immunodeficiency virus (SIV). We show that integrin α4β7 is efficiently incorporated into the envelope of HIV-1 virions. Incorporated α4β7 is functionally active as it binds mucosal addressin cell adhesion molecule-1 (MAdCAM-1), promoting HIV-1 capture by and infection of MAdCAM-expressing cells, which in turn mediate trans-infection of bystander cells. Functional α4β7 is present in circulating virions from HIV-infected patients and SIV-infected macaques, with peak levels during the early stages of infection. In vivo homing experiments documented selective and specific uptake of α4β7 HIV-1 virions by high endothelial venules in the intestinal mucosa. These results extend the paradigm of tissue homing to a retrovirus and are relevant for the pathogenesis, treatment, and prevention of HIV-1 infection.
肠道黏膜是HIV-1复制和CD4 T细胞耗竭的关键解剖部位。因此，在感染猿猴免疫缺陷病毒（SIV）的猕猴中，用抗肠道归巢整合素α4β7的抗体进行体内治疗可减少病毒传播、延缓疾病进展并诱导病毒持续控制。我们发现整合素α4β7能有效地整合到HIV-1病毒颗粒的包膜中。整合的α4β7具有功能活性，因为它能结合黏膜地址素细胞黏附分子-1（MAdCAM-1），促进HIV-1被表达MAdCAM的细胞捕获并感染这些细胞，进而介导旁观者细胞的转染。功能性α4β7存在于HIV感染患者和SIV感染猕猴的循环病毒颗粒中，在感染早期水平达到峰值。体内归巢实验证明肠道黏膜中的高内皮微静脉对α4β7 HIV-1病毒颗粒有选择性和特异性摄取。这些结果将组织归巢的范例扩展到逆转录病毒，对HIV-1感染的发病机制、治疗和预防具有重要意义。
