Abstract
ABSTRACTMacrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted.
Highlights
Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins
We sought to determine whether IFNs from various families could differentially modulate SAMHD1 protein levels or activity and whether these changes would in turn affect HIV-1 infection in macrophages
Our experiments demonstrate that SAMHD1 dephosphorylation at threonine-592 represents a central mechanism of HIV-1 restriction that is common to the three known families of IFNs, though with vastly different efficiencies, as evidenced by the limited potency of IFN-
Summary
Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. We examined the abilities of divergent IFN families to inhibit HIV-1 infection in primary human monocyte-derived macrophages (MDM) and provide mechanistic insight into the major effector function of type I, type II, and type III IFNs. We extended the study to explore the HIV-1 restriction potential of a panel of FDAapproved tyrosine kinase inhibitors (TKI) in an effort to define SAMHD1 as a potential pharmacologic target for anti-HIV-1 efforts. We extended the study to explore the HIV-1 restriction potential of a panel of FDAapproved tyrosine kinase inhibitors (TKI) in an effort to define SAMHD1 as a potential pharmacologic target for anti-HIV-1 efforts These studies show that SAMHD1 serves as the key regulator of HIV-1 infectivity in MDM whose activity is rapidly induced at the level of protein dephosphorylation
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