title: CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21.
abstract: Elite controllers represent a unique group of HIV-1-infected persons with undetectable HIV-1 replication in the absence of antiretroviral therapy. However, the mechanisms contributing to effective viral immune defense in these patients remain unclear. Here, we show that compared with HIV-1 progressors and HIV-1-negative persons, CD4+ T cells from elite controllers are less susceptible to HIV-1 infection. This partial resistance to HIV-1 infection involved less effective reverse transcription and mRNA transcription from proviral DNA and was associated with strong and selective upregulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). Experimental blockade of p21 in CD4+ T cells from elite controllers resulted in a marked increase of viral reverse transcripts and mRNA production and led to higher enzymatic activities of cyclin-dependent kinase 9 (CDK9), which serves as a transcriptional coactivator of HIV-1 gene expression. This suggests that p21 acts as a barrier against HIV-1 infection in CD4+ T cells from elite controllers by inhibiting a cyclin-dependent kinase required for effective HIV-1 replication. These data demonstrate a mechanism of host resistance to HIV-1 in elite controllers and may open novel perspectives for clinical strategies to prevent or treat HIV-1 infection.
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
authors.forename: Huabiao
authors.initials: H
authors.lastname: Chen
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Jinghe
authors.initials: J
authors.lastname: Huang
authors.forename: Thai
authors.initials: T
authors.lastname: Cung
authors.forename: Katherine
authors.initials: K
authors.lastname: Seiss
authors.forename: Jill
authors.initials: J
authors.lastname: Beamon
authors.forename: Mary F
authors.initials: MF
authors.lastname: Carrington
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Porter
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Burke
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.forename: Bethany J
authors.initials: BJ
authors.lastname: Ryan
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: William D
authors.initials: WD
authors.lastname: Cress
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Brass
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication / Q000276:immunology / Q000502:physiology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D012333:RNA, Messenger; D012367:RNA, Viral; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9