title: SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection.
abstract: Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor.
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, Langen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Berger
authors.forename: Andreas F R
authors.initials: AF
authors.lastname: Sommer
authors.forename: Jenny
authors.initials: J
authors.lastname: Zwarg
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamdorf
authors.forename: Karin
authors.initials: K
authors.lastname: Welzel
authors.forename: Nicole
authors.initials: N
authors.lastname: Esly
authors.forename: Sylvia
authors.initials: S
authors.lastname: Panitz
authors.forename: Andreas
authors.initials: A
authors.lastname: Reuter
authors.forename: Irene
authors.initials: I
authors.lastname: Ramos
authors.forename: Asavari
authors.initials: A
authors.lastname: Jatiani
authors.forename: Lubbertus C F
authors.initials: LC
authors.lastname: Mulder
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.forename: Egbert
authors.initials: E
authors.lastname: Flory
mesh_terms: D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D018613:Microscopy, Confocal; D020559:Monomeric GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D020125:Mutation, Missense; D022423:Myeloid Cells / Q000378:metabolism / Q000821:virology*; D009421:Nervous System Malformations / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000076106:SAM Domain and HD Domain-Containing Protein 1; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D018950:Lipopolysaccharide Receptors; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins