Abstract
BackgroundMammalian cells harbour RNA quality control and degradative machineries such as nonsense-mediated mRNA decay that target cellular mRNAs for clearance from the cell to avoid aberrant gene expression. The role of the host mRNA decay pathways in macrophages in the context of human immunodeficiency virus type 1 (HIV-1) infection is yet to be elucidated. Macrophages are directly infected by HIV-1, mediate the dissemination of the virus and contribute to the chronic activation of the inflammatory response observed in infected individuals. Therefore, we characterized the effects of four host mRNA decay proteins, i.e., UPF1, UPF2, SMG6 and Staufen1, on viral replication in HIV-1-infected primary monocyte-derived macrophages (MDMs).ResultsSteady-state expression levels of these host mRNA decay proteins were significantly downregulated in HIV-1-infected MDMs. Moreover, UPF2 and SMG6 inhibited HIV-1 gene expression in macrophages to a similar level achieved by SAMHD1, by directly influencing viral genomic RNA levels. Staufen1, a host protein also involved in UPF1-dependent mRNA decay and that acts at several HIV-1 replication steps, enhanced HIV-1 gene expression in MDMs.ConclusionsThese results provide new evidence for roles of host mRNA decay proteins in regulating HIV-1 replication in infected macrophages and can serve as potential targets for broad-spectrum antiviral therapeutics.
Highlights
Mammalian cells harbour RNA quality control and degradative machineries such as nonsense-mediated mRNA decay that target cellular mRNAs for clearance from the cell to avoid aberrant gene expression
To determine whether the expression of these proteins is modulated during human immunodeficiency virus type 1 (HIV-1) infection, we assessed the levels of Up-frameshift protein 1 (UPF1), UPF2 and SMG6 expression in HIV-1-infected primary monocyte-derived macrophages (MDMs) using an HIV-1 reporter construct called NL4-3-Bal-IRES-heat-stable antigen (HSA) [44,45,46]
Wholecell lysates were collected from HSA-positive (HIV-1-infected cells) and HSA-negative, and the expression levels of UPF1, UPF2 and SMG6 were quantified by Western blotting
Summary
Mammalian cells harbour RNA quality control and degradative machineries such as nonsense-mediated mRNA decay that target cellular mRNAs for clearance from the cell to avoid aberrant gene expression. Macrophages are cells of the myeloid lineage that serve important functions in the host innate immune response They recognise and phagocytose invading pathogens and play many roles in tissue development, homeostasis and repair [1]. Macrophages play multiple roles in human immunodeficiency virus type 1 (HIV-1) pathogenesis (reviewed in [4,5,6]) as they express the host cell surface receptors CD4 and CCR5 required for HIV-1 entry and can be directly infected by HIV-1 [7, 8] They promote the dissemination and cell-to-cell transmission of HIV-1 via virological synapses [9,10,11] and they can be infected in trans by the selective capture and engulfment of HIV1-infected CD4+ T cells [12]. They directly contribute to pathogenesis via the activation of inflammatory pathways resulting in the cognitive dysfunction, respiratory dysfunction, cardiovascular disease and microbial translocation in the intestine associated with HIV-1 infection (reviewed in [5])
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