title: A cell-intrinsic inhibitor of HIV-1 reverse transcription in CD4(+) T cells from elite controllers.
abstract: HIV-1 reverse transcription represents the predominant target for pharmacological inhibition of viral replication, but cell-intrinsic mechanisms that can block HIV-1 reverse transcription in a clinically significant way are poorly defined. We find that effective HIV-1 reverse transcription depends on the phosphorylation of viral reverse transcriptase by host cyclin-dependent kinase (CDK) 2 at a highly conserved Threonine residue. CDK2-dependent phosphorylation increased the efficacy and stability of viral reverse transcriptase and enhanced viral fitness. Interestingly, p21, a cell-intrinsic CDK inhibitor that is upregulated in CD4(+) T cells from "elite controllers," potently inhibited CDK2-dependent phosphorylation of HIV-1 reverse transcriptase and significantly reduced the efficacy of viral reverse transcription. These data suggest that p21 can indirectly block HIV-1 reverse transcription by inhibiting host cofactors supporting HIV-1 replication and identify sites of viral vulnerability that are effectively targeted in persons with natural control of HIV-1 replication.
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA.|Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Leng
authors.affiliation: Department of Chemistry, York College and the Graduate Center, City University of New York, New York, NY, USA.
authors.forename: Hsin-Pin
authors.initials: HP
authors.lastname: Ho
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA.|Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Buzon
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.|Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.affiliation: Department of Chemistry, York College and the Graduate Center, City University of New York, New York, NY, USA.
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Chang
authors.affiliation: Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D016022:Case-Control Studies; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D048348:Reverse Transcription; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase