Delivery of the HSV-1 genome through the nuclear pore complex

• Applicant: Professor Dr. Victor Shahin
• Subject Area: Virology
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 186214281

Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen. Its replication involves an essential multi-step process in which the virus DNA is uncoated and delivered into the nucleus of the infected cell. Uncoating occurs when a parental, fairly stiff (~ 540 pN/nm) and large (125 nm in diameter) capsid binds to a ~ 100 times softer, 100 nm wide nuclear pore complex (NPC) and delivers its large (152 kbp, 45 µm long) DNA through the 10 nm wide and 50 nm long NPC channel into the nucleoplasm. This so far poorly understood process can be subdivided into three distinct steps being i) docking at the NPC, ii) capsid opening and DNA release, and iii) DNA transport through the NPC. Each of these steps raises numerous questions that remain unanswered as yet. Our working hypotheses are as follows: 1) the incoming HSV-1 capsid interacts specifically with NPC proteins and significant changes in NPC conformation and function set the stage for HSV-1 genome uncoating. 2) The stiff capsid softens prior to genome release. 3) We assume that the enclosed viral genome is pressurised and that genome release out of the capsid occurs fast. 4) Genome translocation through the NPC channel may partly be pressure-driven but is likely to be largely mediated by the NPC. The aim of this project is to corroborate these hypotheses and address the numerous open questions in the individual steps of uncoating, in order to elucidate the mechanisms underlying this key multi-step process.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Joachim E. Kühn