title: Small-molecule inhibition of human immunodeficiency virus type 1 replication by specific targeting of the final step of virion maturation.
abstract: Despite the effectiveness of currently available human immunodeficiency virus type 1 (HIV-1) therapies, a continuing need exists for new drugs to treat HIV-1 infection. We investigated the mechanism by which 3-O-[3',3'-dimethylsuccinyl]-betulinic acid (DSB) inhibits HIV-1 replication. DSB functions at a late stage of the virus life cycle but does not inhibit the HIV-1 protease in vitro or interfere with virus assembly or release. DSB specifically delays the cleavage of Gag between the capsid (CA) and p2, resulting in delayed formation of the mature viral core and reduced HIV-1 infectivity. Replication of simian immunodeficiency virus (SIV) was resistant to DSB; however, a chimeric SIV carrying CA-p2 sequences from HIV-1 was inhibited by the drug, indicating that susceptibility to DSB maps to the CA-p2 region of the HIV-1 Gag protein. A single point mutation at the CA-p2 cleavage site of HIV-1 conferred strong resistance to DSB, confirming the target of the drug. HIV-1 strains that are resistant to a variety of protease inhibitors were sensitive to DSB. These findings indicate that DSB specifically protects the CA-p2 cleavage site from processing by the viral protease during virion maturation, thereby revealing a novel mechanism for pharmacologic inhibition of HIV-1 replication.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Xiong
authors.initials: X
authors.lastname: Yuan
authors.forename: David
authors.initials: D
authors.lastname: Dismuke
authors.forename: Brett M
authors.initials: BM
authors.lastname: Forshey
authors.forename: Christopher
authors.initials: C
authors.lastname: Lundquist
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
authors.forename: Chin Ho
authors.initials: CH
authors.lastname: Chen
mesh_terms: D001483:Base Sequence; D002213:Capsid / Q000737:chemistry; D002460:Cell Line; D015683:Gene Products, gag / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D013449:Sulfonamides / Q000494:pharmacology*; D014771:Virion / Q000187:drug effects* / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects*; D000096926:Benzenesulfonamides
chemical_list: D015683:Gene Products, gag; D013449:Sulfonamides; C007563:1,2-di-(4-sulfamidophenyl)-4-butylpyrazolidine-3,5-dione; D000096926:Benzenesulfonamides