Provirus

Receptor

Virus

Integrase inhibitor

Biology

Gene

Integrase

Viral replication

Genome

Viral load

Virology

Allosteric regulation

Antiretroviral therapy

Computational biology

Cell biology

Genetics

Nature Reviews Microbiology

A hallmark of retroviral replication is establishment of the proviral state, wherein a DNA copy of the viral RNA genome is stably incorporated into a host cell chromosome. Integrase is the viral enzyme responsible for the catalytic steps involved in this process, and integrase strand transfer inhibitors are widely used to treat people living with HIV. Over the past decade, a series of X-ray crystallography and cryogenic electron microscopy studies have revealed the structural basis of retroviral DNA integration. A variable number of integrase molecules congregate on viral DNA ends to assemble a conserved intasome core machine that facilitates integration. The structures additionally informed on the modes of integrase inhibitor action and the means by which HIV acquires drug resistance. Recent years have witnessed the development of allosteric integrase inhibitors, a highly promising class of small molecules that antagonize viral morphogenesis. In this Review, we explore recent insights into the organization and mechanism of the retroviral integration machinery and highlight open questions as well as new directions in the field. A hallmark of retroviral replication is establishment of the proviral state, wherein a DNA copy of the viral RNA genome is stably incorporated into a host cell chromosome by the viral enzyme integrase. In this Review, Maertens, Engelman and Cherepanov explore the structure and function of retroviral integrase and how this knowledge is informing the development of integrase inhibitors for the treatment of HIV infection.

Structure and function of retroviral integrase