HIV-1 gp120 Glycoprotein Interacting with Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN) Down-Regulates Tight Junction Proteins to Disrupt the Blood Retinal Barrier and Increase Its Permeability.
Approximately 70% of HIV-1 infected patients acquire ocular opportunistic infections and manifest eye disorders during the course of their illness. The mechanisms by which pathogens invade the ocular site, however, are unclear. Under normal circumstances, vascular endothelium and retinal pigment epithelium (RPE), which possess a well developed tight junction complex, form the blood-retinal barrier (BRB) to prevent pathogen invasion. We hypothesize that disruption of the BRB allows pathogen entry into ocular sites. The hypothesis was tested using in vitro models. We discovered that human RPE cells could bind to either HIV-1 gp120 glycoproteins or HIV-1 viral particles. Furthermore, the binding was mediated by dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) expressed on RPE cells. Upon gp120 binding to DC-SIGN, cellular NF-κB signaling was triggered, leading to the induction of matrix metalloproteinases, which subsequently degraded tight junction proteins and disrupted the BRB integrity. DC-SIGN knockdown or prior blocking with a specific antibody abolished gp120-induced matrix metalloproteinase expression and reduced the degradation of tight junction proteins. This study elucidates a novel mechanism by which HIV, type 1 invades ocular tissues and provides additional insights into the translocation or invasion process of ocular complication-associated pathogens.
From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
Yi-Wen
YW
Qian
From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
Chuan
C
Li
the Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology and.
Ai-Ping
AP
Jiang
From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
Shengfang
S
Ge
From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
Ping
P
Gu
From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
Xianqun
X
Fan
the Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
Tai-Sheng
TS
Li
the Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology and.|Viral Disease and Vaccine Translational Research Unit and Vaccine Center, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China, and.
Xia
X
Jin
the Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology and jh_wang@sibs.ac.cn.
Jian-Hua
JH
Wang
From the Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China, ophwzl@163.com.
Zhi-Liang
ZL
Wang
D001813:Blood-Retinal Barrier / Q000378:metabolism* / Q000821:virology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D062725:Tight Junction Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
DC-SIGN; HIV; HIV-1; blood-retinal barrier; glycoprotein; matrix metalloproteinase (MMP); retina; tight junction; tight junction protein