Multifunctional facets of retrovirus integrase

Abstract

The retrovirus integrase (IN) is responsible for integration of the reverse transcribed linear cDNA into the host DNA genome. First, IN cleaves a dinucleotide from the 3’ OH blunt ends of the viral DNA exposing the highly conserved CA sequence in the recessed ends. IN utilizes the 3’ OH ends to catalyze the concerted integration of the two ends into opposite strands of the cellular DNA producing 4 to 6 bp staggered insertions, depending on the retrovirus species. The staggered ends are repaired by host cell machinery that results in a permanent copy of the viral DNA in the cellular genome. Besides integration, IN performs other functions in the replication cycle of several studied retroviruses. The proper organization of IN within the viral internal core is essential for the correct maturation of the virus. IN plays a major role in reverse transcription by interacting directly with the reverse transcriptase and by binding to the viral capsid protein and a cellular protein. Recruitment of several other host proteins into the viral particle are also promoted by IN. IN assists with the nuclear transport of the preintegration complex across the nuclear membrane. With several retroviruses, IN specifically interacts with different host protein factors that guide the preintegration complex to preferentially integrate the viral genome into specific regions of the host chromosomal target. Human gene therapy using retrovirus vectors is directly affected by the interactions of IN with these host factors. Inhibitors directed against the human immunodeficiency virus (HIV) IN bind within the active site of IN containing viral DNA ends thus preventing integration and subsequent HIV/AIDS.

Keywords: Retrovirus integrase, Integration, Host factors, Atomic structure, Human immunodeficiency virus integrase inhibitors

Core tip: This review examines the multifunctional properties of retrovirus integrase (IN) besides its key function of integrating the viral DNA into host chromosomes. IN has a major role in the maturation of the virus, reverse transcription and nuclear transport of the preintegration complex. IN binds to cellular cofactors for uncoating of the core and to other cellular proteins that guide the preintegration complex to preferred regions on the host genome for integration. Understanding these IN functions has resulted in the production of clinical IN strand transfer inhibitors to prevent human immunodeficiency virus (HIV/AIDS) and development of retrovirus vectors for human gene therapy.