virus evolution reveals an exclusive role for ledgfp75 in chromosomal tethering of hiv病毒进化了独家角色ledgfp75染色体拘束的艾滋病毒.pdfVIP

Virus Evolution Reveals an Exclusive Role for LEDGF/p75 in Chromosomal Tethering of HIV 1[ 1[ 2 1 3 3 Anneleen Hombrouck , Jan De Rijck , Jelle Hendrix , Linos Vandekerckhove , Arnout Voet , Marc De Maeyer , 1 2 1 1 1* Myriam Witvrouw , Yves Engelborghs , Frauke Christ , Rik Gijsbers , Zeger Debyser 1 The Laboratory for Molecular Virology and Gene Therapy, KULeuven and IRC KULAK, Leuven, Flanders, Belgium, 2 The Laboratory for Biomolecular Dynamics, KULeuven, Leuven, Flanders, Belgium, 3 The Laboratory for Biomolecular Modelling, KULeuven, Leuven, Flanders, Belgium Retroviruses by definition insert their viral genome into the host cell chromosome. Although the key player of retroviral integration is viral integrase, a role for cellular cofactors has been proposed. Lentiviral integrases use the cellular protein LEDGF/p75 to tether the preintegration complex to the chromosome, although the existence of alternative host proteins substituting for the function of LEDGF/p75 in integration has been proposed. Truncation mutants of LEDGF/p75 lacking the chromosome attachment site strongly inhibit HIV replication by competition for the interaction with integrase. In an attempt to select HIV strains that can overcome the inhibition, we now have used T- cell lines that stably express a C-terminal fragment of LEDGF/p75. Despite resistance development, the affinity of integrase for LEDGF/p75 is reduced and replication kinetics in human primary T cells is impaired. Detection of the integrase mutations A128T and E170G at key positions in the LEDGF/p75–integrase interface provides in v