title: Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells.
abstract: HIV-1 integrase (IN) is the target for two classes of antiretrovirals: i) the integrase strand-transfer inhibitors (INSTIs) and ii) the non-catalytic site integrase inhibitors (NCINIs). NCINIs bind at the IN dimer interface and are thought to interfere primarily with viral DNA (vDNA) integration in the target cell by blocking IN-vDNA assembly as well as the IN-LEDGF/p75 interaction. Herein we show that treatment of virus-producing cells, but not of mature virions or target cells, drives NCINI antiviral potency. NCINIs target an essential late-stage event in HIV replication that is insensitive to LEDGF levels in the producer cells. Virus particles produced in the presence of NCINIs displayed normal Gag-Pol processing and endogenous reverse transcriptase activity, but were defective at initiating vDNA synthesis following entry into the target cell. NCINI-resistant virus carrying a T174I mutation in the IN dimer interface was less sensitive to the compound-induced late-stage effects, including the reverse transcription block. Wild-type, but not T174I virus, produced in the presence of NCINIs exhibited striking defects in core morphology and an increased level of IN oligomers that was not observed upon treatment of mature cell-free particles. Collectively, these results reveal that NCINIs act through a novel mechanism that is unrelated to the previously observed inhibition of IN activity or IN-LEDGF interaction, and instead involves the disruption of an IN function during HIV-1 core maturation and assembly.
authors.affiliation: Gilead Sciences Inc., Foster City, California, United States of America.
authors.forename: Mini
authors.initials: M
authors.lastname: Balakrishnan
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Yant
authors.forename: Luong
authors.initials: L
authors.lastname: Tsai
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Sullivan
authors.forename: Rujuta A
authors.initials: RA
authors.lastname: Bam
authors.forename: Angela
authors.initials: A
authors.lastname: Tsai
authors.forename: Anita
authors.initials: A
authors.lastname: Niedziela-Majka
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Stray
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D024882:Drug Resistance, Viral; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors; D019427:HIV Integrase / Q000235:genetics* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000187:drug effects / Q000235:genetics; D019065:Virus Assembly / Q000187:drug effects; D016662:Virus Integration / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; C504649:PSIP1 protein, human; D014157:Transcription Factors; D008156:Luciferases; D019427:HIV Integrase; D054303:HIV Reverse Transcriptase; C514801:p31 integrase protein, Human immunodeficiency virus 1
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