title: The Expression of Functional Vpx during Pathogenic SIVmac Infections of Rhesus Macaques Suppresses SAMHD1 in CD4+ Memory T Cells.
abstract: For nearly 20 years, the principal biological function of the HIV-2/SIV Vpx gene has been thought to be required for optimal virus replication in myeloid cells. Mechanistically, this Vpx activity was recently reported to involve the degradation of Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1) in this cell lineage. Here we show that when macaques were inoculated with either the T cell tropic SIVmac239 or the macrophage tropic SIVmac316 carrying a Vpx point mutation that abrogates the recruitment of DCAF1 and the ensuing degradation of endogenous SAMHD1 in cultured CD4+ T cells, virus acquisition, progeny virion production in memory CD4+ T cells during acute infection, and the maintenance of set-point viremia were greatly attenuated. Revertant viruses emerging in two animals exhibited an augmented replication phenotype in memory CD4+ T lymphocytes both in vitro and in vivo, which was associated with reduced levels of endogenous SAMHD1. These results indicate that a critical role of Vpx in vivo is to promote the degradation of SAMHD1 in memory CD4+ T lymphocytes, thereby generating high levels of plasma viremia and the induction of immunodeficiency.
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shingai
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Welbourn
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Acharya
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Eri
authors.initials: E
authors.lastname: Miyagi
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Plishka
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Alicia
authors.initials: A
authors.lastname: Buckler-White
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebel
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Martin
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D017353:Gene Deletion; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007156:Immunologic Memory; D008253:Macaca mulatta; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D000076106:SAM Domain and HD Domain-Containing Protein 1; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014766:Viremia / Q000276:immunology / Q000378:metabolism / Q000821:virology
chemical_list: D010446:Peptide Fragments; D011994:Recombinant Proteins; C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins