TY - JOUR
T1 - MicroRNAs upregulated during HIV infection target peroxisome biogenesis factors
T2 - Implications for virus biology, disease mechanisms and neuropathology
AU - Xu, Zaikun
AU - Asahchop, Eugene L.
AU - Branton, William G.
AU - Gelman, Benjamin B.
AU - Power, Christopher
AU - Hobman, Tom C.
N1 - Funding Information:
Operating funds to support research and tissue procurement were from: Team grant on HIV/AIDS and comorbidities (TCO125271) from the Canadian Institutes of Health Research (http://www.cihr-irsc.gc.ca/e/193.html) to CP and TCH. The National NeuroAIDS Tissue Consortium (http://www.ninds.nih.gov/find_people/voluntary_orgs/volorg725.htm) provided human brain tissue specimens and is supported by the following cooperative agreements from National Institutes of Health: U24MH100928; U24MH100929; U24MH100930; U24MH100931; U24MH100925 to BBG. Salary support from the Canada Research Chairs program (http://www.chairschaires. gc.ca/home-accueil-eng.aspx) to CP and TCH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Valeria Mancinelli and Eileen Reklow for technical assistance.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.ppat.1006360
DO - 10.1371/journal.ppat.1006360
M3 - Article
C2 - 28594894
AN - SCOPUS:85021822686
VL - 13
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 6
M1 - e1006360
ER -