A SAMHD1 mutation associated with Aicardi–Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV‐1 from its ability to downmodulate type I interferon in humans

• Published in: Human mutation Vol. 38; no. 6; pp. 658 - 668
• Main Authors: White, Tommy E., Brandariz‐Nuñez, Alberto, Martinez‐Lopez, Alicia, Knowlton, Caitlin, Lenzi, Gina, Kim, Baek, Ivanov, Dmitri, Diaz‐Griffero, Felipe
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.06.2017
• Subjects: Aicardi–Goutières syndrome; Antiviral activity; CD4 antigen; Dendritic cells; Encephalopathy; Genetic disorders; HIV‐1; Inflammation; Interferon; Lymphocytes T; Macrophages; Mutation; Neurological complications; Neurological disorders; Proteins; Ribonucleic acid; RNA; SAMHD1; HIV-1; SAMHD1; interferon; Aicardi-Goutières syndrome
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23201

Mutations in the human SAMHD1 gene are known to correlate with the development of the Aicardi–Goutières syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production of type I interferon (IFN); this evidence has led to the concept that the SAMHD1 protein negatively regulates the type I IFN response. Additionally, the SAMHD1 protein has been shown to prevent efficient HIV‐1 infection of macrophages, dendritic cells, and resting CD4+ T cells. To gain insights on the SAMHD1 molecular determinants that are responsible for the deregulated production of type I IFN, we explored the biochemical, cellular, and antiviral properties of human SAMHD1 mutants known to correlate with the development of AGS. Most of the studied SAMHD1 AGS mutants exhibit defects in the ability to oligomerize, decrease the levels of cellular deoxynucleotide triphosphates in human cells, localize exclusively to the nucleus, and restrict HIV‐1 infection. At least half of the tested variants preserved the ability to be degraded by the lentiviral protein Vpx, and all of them interacted with RNA. Our investigations revealed that the SAMHD1 AGS variant p.G209S preserve all tested biochemical, cellular, and antiviral properties, suggesting that this residue is a determinant for the ability of SAMHD1 to negatively regulate the type I IFN response in human patients with AGS. Overall, our work genetically separated the ability of SAMHD1 to negatively regulate the type I IFN response from its ability to restrict HIV‐1. SAMHD1 has two genetically separable functions: 1.‐ restricts HIV‐1. 2‐ negatively regulates the type I IFN response in humans, and avoids the development of Aicardi‐Goutières syndrome.