MicroRNAs upregulated during HIV infection target peroxisome biogenesis factors: Implications for virus biology, disease mechanisms and neuropathology

PLoS Pathogens

Zaikun Xu¹  Tom C. Hobman²  William G. Branton³  Eugene L. Asahchop³  Christopher Power³  Benjamin B. Gelman⁴ 

[1] Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada;Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Alberta, Canada;Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America

关键词: MicroRNAs;    Peroxisomes;    HIV-1;    Luciferase;    HIV;    Biosynthesis;    3' UTR;    Macrophages;   

DOI  :  10.1371/journal.ppat.1006360

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

HIV-associated neurocognitive disorders (HAND) represent a spectrum neurological syndrome that affects up to 25% of patients with HIV/AIDS. Multiple pathogenic mechanisms contribute to the development of HAND symptoms including chronic neuroinflammation and neurodegeneration. Among the factors linked to development of HAND is altered expression of host cell microRNAs (miRNAs) in brain. Here, we examined brain miRNA profiles among HIV/AIDS patients with and without HAND. Our analyses revealed differential expression of 17 miRNAs in brain tissue from HAND patients. A subset of the upregulated miRNAs (miR-500a-5p, miR-34c-3p, miR-93-3p and miR-381-3p), are predicted to target peroxisome biogenesis factors (PEX2, PEX7, PEX11B and PEX13). Expression of these miRNAs in transfected cells significantly decreased levels of peroxisomal proteins and concomitantly decreased peroxisome numbers or affected their morphology. The levels of miR-500a-5p, miR-34c-3p, miR-93-3p and miR-381-3p were not only elevated in the brains of HAND patients, but were also upregulated during HIV infection of primary macrophages. Moreover, concomitant loss of peroxisomal proteins was observed in HIV-infected macrophages as well as in brain tissue from HIV-infected patients. HIV-induced loss of peroxisomes was abrogated by blocking the functions of the upregulated miRNAs. Overall, these findings point to previously unrecognized miRNA expression patterns in the brains of HIV patients. Targeting peroxisomes by up-regulating miRNAs that repress peroxisome biogenesis factors may represent a novel mechanism by which HIV-1 subverts innate immune responses and/or causes neurocognitive dysfunction.

【 授权许可】

CC BY