Phosphodiesterase 8a Supports HIV-1 Replication in Macrophages at the Level of Reverse Transcription

被引:4
作者
Booiman, Thijs
Jimenez, Viviana Cobos
van Dort, Karel A.
van't Wout, Angelique B.
Kootstra, Neeltje A. [1 ]
机构
[1] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Landsteiner Lab,Sanquin Res, NL-1105 AZ Amsterdam, Netherlands
来源
PLOS ONE | 2014年 / 9卷 / 10期
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCYTE-DERIVED MACROPHAGES; PRODUCTIVE INFECTION; TYPE-1; REPLICATION; CCR5; EXPRESSION; LYMPHOID-TISSUE; T-CELLS; TRANSMISSION; SAMHD1; PERSISTENCE;
D O I
10.1371/journal.pone.0109673
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: HIV-1 infected macrophages play a key role in HIV-1 infection. Even during anti-retroviral treatment, macrophages keep producing virus due to suboptimal tissue penetration and reduced efficacy of antiretrovirals. It is therefore of major importance to understand which host factors are involved in HIV-1 replication in macrophages. Previously, we have shown that genetic polymorphisms in phosphodiesterase 8a (PDE8A) are strongly associated with HIV-1 replication in these cells. Here we analyzed the mechanism and regulation of PDE8A in HIV-1 replication in macrophages. Results: PDE8A mRNA expression strongly increases upon differentiation of monocytes into macrophages, which corresponds to the increased susceptibility of mature macrophages to HIV-1. In parallel, expression of microRNA miR-1455p, predicted to target PDE8A mRNA, strongly decreased. The interaction of miR-145-5p with the 39 UTR of PDE8A mRNA could be experimentally validated, suggesting that indeed miR-145-5p can regulate PDE8A expression levels. Knockdown of PDE8A in macrophages resulted in a decrease in total HIV-1 replication and proviral DNA levels. These observations confirm that PDE8A regulates HIV-1 replication in macrophages and that this effect is mediated through early steps in the viral replication cycle. Conclusions: PDE8A is highly expressed in macrophages, and its expression is regulated by miR-145-5p. Our findings strongly suggest that PDE8A supports HIV-1 replication in macrophages and that this effect is mediated at the level of reverse transcription.
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页数:9
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