An essential role for LEDGF/p75 in HIV integration.
Chromosomal integration enables human immunodeficiency virus (HIV) to establish a permanent reservoir that can be therapeutically suppressed but not eradicated. Participation of cellular proteins in this obligate replication step is poorly understood. We used intensified RNA interference and dominant-negative protein approaches to show that the cellular transcriptional coactivator lens epithelium-derived growth factor (LEDGF)/p75 (p75) is an essential HIV integration cofactor. The mechanism requires both linkages of a molecular tether that p75 forms between integrase and chromatin. Fractionally minute levels of endogenous p75 are sufficient to enable integration, showing that cellular factors that engage HIV after entry may elude identification in less intensive knockdowns. Perturbing the p75-integrase interaction may have therapeutic potential.
Llano
Manuel
M
Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Saenz
Dyana T
DT
Meehan
Anne
A
Wongthida
Phonphimon
P
Peretz
Mary
M
Walker
William H
WH
Teo
Wulin
W
Poeschla
Eric M
EM
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D019427:HIV Integrase / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016662:Virus Integration; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D036341:Intercellular Signaling Peptides and Proteins; C504649:PSIP1 protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C051610:hepatoma-derived growth factor; D019427:HIV Integrase