A 2026 Crick PhD project with Peter Cherepanov.
A retrovirus, such as HIV, must insert a DNA replica of its genome into a host cell chromosome to establish successful infection. This essential process is catalyzed by integrase, a specialized DNA recombinase carried by the virus (reviewed in [1]). To accomplish this function, a multimer of integrase assembles at the ends of viral DNA forming a highly stable complex termed intasome [2, 3]. Upon nuclear entry, the intasome inserts 3’ ends of viral DNA molecule into chromosomal DNA [4, 5].
Genetic evidence accumulated over the past 30 years strongly suggests that integrase performs another essential function prior to viral DNA synthesis. For HIV-1 to become infectious, the virion must undergo maturation to form a conical capsid core that encloses the RNA genome and protects viral nucleic acids upon entry into a new target cell. A class of mutations in HIV-1 integrase, as well as treatment with allosteric HIV-1 integrase inhibitors result in formation of eccentric virions, where viral nucleoid is mislocalized outside the capsid core. The malformation renders the virus completely non-infectious due to its inability to complete reverse transcription upon fusion with a new target cell. Very recently, we have determined cryo-EM structures of integrase bound to RNA in vitro as well as inside intact viral cores, which revealed that integrase forms an RNA-binding filament associated with the lumen of HIV-1 capsid core (Submitted for publication).
While recent research unraveled many structural and mechanistic details of these processes, we are far from understanding the rules of engagement between integrase and the lumen of viral capsid core and nuclear environment. Does viral capsid lattice template intasome assembly and how is intasome released from the capsid core? How is the intasome trafficked in the cell, and how does the virus select appropriate chromosomal locations for integration? How do the recent intasome crystal and cryo-EM structures relate to the native retroviral pre-integration complex? These are examples of the sorts of projects that are available in our laboratory. Only one studentship is available with this group and the precise project will be decided on consultation with the supervisor.
This project would suit candidates with background in biochemistry and strong interest in structural biology and virology.