Interplay of ancestral non-primate lentiviruses with the virus-restricting SAMHD1 proteins of their hosts

• Type of Material: Article
• Authors: Sarah A. Mereby, Emory University; Tatsuya Maehigashi, Emory University; Jessica M. Holler, Emory University; Dong-Hyun Kim, Kyung-Hee University; Raymond Schinazi, Emory University; Baek Kim, Emory University
• Language: English
• Date: 2018-10-19
• Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Mereby et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA118.004567
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 293
• Issue: 42
• Start Page: 16402
• End Page: 16412
• Grant/Funding Information: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; This work was supported by National Institutes of Health Grants AI136581 (to B. K.), GM104198 (to B. K.), and MH116695 (to R. F. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: nucleotide; GENE-TRANSFER; DENDRITIC CELLS; Science & Technology; Life Sciences & Biomedicine; dNTPase; Biochemistry & Molecular Biology; lentivirus; HUMAN-IMMUNODEFICIENCY-VIRUS; SAM domain and HD domain-containing protein 1 (SAMHD1); VECTORS; reverse transcription; HIV-1 INFECTION; MOUSE SAMHD1; antiviral defense; INFECTIOUS-ANEMIA VIRUS; macrophage; IN-VIVO; proteosomal degradation; TISSUE MACROPHAGES; immunodeficiency virus; REVERSE TRANSCRIPTION
• Research Categories: Health Sciences, Immunology

Abstract

Lentiviruses infect both dividing CD4+ T cells and nondividing myeloid cells, and the infected myeloid cells serve as longliving viral reservoirs. Host sterile alpha motif- and histidineaspartate domain-containing protein 1 (SAMHD1) kinetically restricts reverse transcription of primate lentiviruses, including human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus (SIV), in nondividing myeloid cells. SAMHD1 enforces this restriction through its dNTP triphosphohydrolase (dNTPase) activity that depletes cellular dNTPs. Some primate lentiviruses, such as HIV-2, SIVsm, and SIVagm, counteract SAMHD1 restriction by using their viral accessory proteins (Vpx or Vpr) that induce the proteosomal degradation of SAMHD1 and increase dNTP levels. SAMHD1 is conserved among non-primate mammals such as cats, cows, and horses that also carry their own lentiviruses (feline and bovine immunodeficiency viruses and equine infectious anemia viruses, respectively). However, whether these viruses also target SAMHD1 is unknown. Here, we tested whether these ancestral non-primate lentiviruses also can counteract their host SAMHD1 proteins by promoting their proteosomal degradation. Using biochemical and various cell-based assays, we observed that SAMHD1 proteins from the non-primate host species display dGTP-dependent dNTPase activity, but that the non-primate lentiviruses fail to proteosomally degrade the SAMHD1 proteins of their hosts. Our findings suggest that accessory protein-mediated proteosomal degradation of SAMHD1 did not exist among the ancestral non-primate lentiviruses and was uniquely gained by some primate lentiviruses after their transmission to primate species.