Dario Passos – Salk Institute for Biological Studies
Still as a major global public health issue, the acquired immune deficiency syndrome (AIDS) is estimated to strike over 36 million people around the globe. Strikingly, around 40% of the infected people are not aware that they have the virus. In addition, only 18.1 million are currently accessing antiretroviral therapy (ART).
The human immunodeficiency virus type-1 (HIV-1), like all retroviruses, irreversibly inserts a viral DNA (vDNA) copy of its RNA genome into host target DNA (tDNA). Integration is mediated by the intasome, a higher-order nucleoprotein complex composed of viral integrase (IN) and the ends of linear vDNA. HIV-1 intasomes have been refractory to high-resolution structural studies despite considerable effort. Here, we present the first high-resolution cryo-electron microscopy (cryoEM) structure of a tetrameric HIV-1 intasome and a higher-order form that adopts distinct domain rearrangements. The unique manner of HIV-1 intasome assembly highlights how HIV-1 can use the common retroviral intasome core architecture to accommodate different IN domain modules for integration.
The highly effective second generation drug currently approved for the treatment of AIDS has been rationally designed using the prototype foamy virus (PFV) as template. The high-resolution structure of the HIV-1 intasome thus provide a critical information for the design of more efficient drugs as well as better understanding of drug activity and resistance.