Abstract

BackgroundHIV-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.ResultsPDE8A 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-145-5p, predicted to target PDE8A mRNA, strongly decreased. The interaction of miR-145-5p with the 3′ 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.ConclusionsPDE8A 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.

Highlights

  • Macrophages play a key role in HIV-1 infection

  • To determine whether phosphodiesterase 8a (PDE8A) plays a role in the differential susceptibility of macrophages during differentiation, PDE8A mRNA expression was analyzed in freshly isolated monocytes and macrophages derived from 31 healthy blood donors

  • We analyzed whether differential expression of PDE8A during cytokine activation of macrophages may contribute to the decreased susceptibility of these cells to HIV-1 infection

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Summary

Introduction

Macrophages play a key role in HIV-1 infection. They are among the first cells that encounter HIV-1 upon transmission and once infected they facilitate spread of the virus to CD4+ T-cells [1,2,3,4,5,6,7]. Infected macrophages remain a source of residual virus production during treatment due to the low efficacy of cART, combined with the suboptimal tissue penetration of the drugs [10,11,12,13,14,15]. In addition to their contribution to the viral reservoir, HIV-1 infected macrophages play a crucial role in several AIDS related pathologies such as HIV-1 associated dementia, AIDS-related non-Hodgkin lymphoma and cardiovascular diseases [16,17,18,19]. We analyzed the mechanism and regulation of PDE8A in HIV-1 replication in macrophages

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