title: SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.
abstract: Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.
authors.affiliation: Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hanna-Mari
authors.initials: HM
authors.lastname: Baldauf
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Pan
authors.forename: Elina
authors.initials: E
authors.lastname: Erikson
authors.forename: Sarah
authors.initials: S
authors.lastname: Schmidt
authors.forename: Waaqo
authors.initials: W
authors.lastname: Daddacha
authors.forename: Manja
authors.initials: M
authors.lastname: Burggraf
authors.forename: Kristina
authors.initials: K
authors.lastname: Schenkova
authors.forename: Ina
authors.initials: I
authors.lastname: Ambiel
authors.forename: Guido
authors.initials: G
authors.lastname: Wabnitz
authors.forename: Thomas
authors.initials: T
authors.lastname: Gramberg
authors.forename: Sylvia
authors.initials: S
authors.lastname: Panitz
authors.forename: Egbert
authors.initials: E
authors.lastname: Flory
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Landau
authors.forename: Serkan
authors.initials: S
authors.lastname: Sertel
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
mesh_terms: D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D015498:HIV-2 / Q000235:genetics / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009421:Nervous System Malformations / Q000235:genetics / Q000821:virology; D048348:Reverse Transcription / Q000235:genetics; D000076106:SAM Domain and HD Domain-Containing Protein 1; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000235:genetics / Q000254:growth & development; D014779:Virus Replication; D000086082:Viroporin Proteins
chemical_list: D054298:Human Immunodeficiency Virus Proteins; D020559:Monomeric GTP-Binding Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C484280:SAMHD1 protein, human