HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy.
The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical-basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Suiyi
S
Tan
1] School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China [2] Department of Pharmacy, Guangdong Provincial Stomatological Hospital, Guangzhou, China.
Heng
H
Duan
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Tianrong
T
Xun
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Wei
W
Ci
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Jiayin
J
Qiu
1] School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China [2] Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA.
Fei
F
Yu
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Xuyan
X
Zhao
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Linxuan
L
Wu
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Lin
L
Li
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, China.
Lu
L
Lu
1] School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China [2] Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA [3] Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, China.
Shibo
S
Jiang
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Shuwen
S
Liu
D018988:Bacterial Translocation; D015153:Blotting, Western; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D010539:Permeability; D012164:Retinal Diseases / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D055213:Retinal Pigment Epithelium / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000502:physiology
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015699:HIV Envelope Protein gp120; D015850:Interleukin-6; D062725:Tight Junction Proteins