Study shows how herpes virus escapes from cell nucleus

Protein complex helps virus exit cell after reproducing so infection can progress. Results published in Cell pave way to search for inhibitors.

By Karina Toledo  |  Agência FAPESP – The mechanism used by the oral herpes simplex virus (HSV-1) to escape from the nucleus of its host cell after replicating has been described in two articles published by the journal Cell.

The strategy consists of secreting two proteins, pUL31 and pUL34, which interact to form a vesicle. This protein complex wraps itself around the virus and transports it out of the nucleus, enabling it to infect another cell – and so the disease progresses.

“Detailed knowledge of this mechanism opens a door to new studies designed to discover whether there are other types of virus and other molecules that are transported out of the nucleus in a similar manner. Moreover, it enables us to think about compounds capable of inhibiting synthesis of these proteins so as to prevent viral egress and progress of the infection,” said Juliana Cheleski Wiggers, a Brazilian member of the international research group led by Kay Grünewald at Oxford University in England.

With support from FAPESP, Wiggers was doing research at the University of São Paulo’s São Carlos Physics Institute (IFSC-USP) when she was awarded a one-year research internship in Professor Grünewald’s laboratory starting in 2014.

At Oxford, Wiggers learned a number of techniques, ranging from electron microscopy to tomography and fluorescence microscopy, used by the group to explore how the herpes virus escapes from the cell.

Like other viruses, HSV-1 is a cellular parasite. In order to reproduce, it must infect a target cell and introduce its genetic material into the nucleus.

The virus then takes control of the cellular metabolism, switching off most genes and making use of substances that it finds in the intracellular medium to multiply its own genetic material. In doing so, it manufactures capsids, or protein coatings that protect the nucleic acids in the new viruses created.

Once reproduction is over, the original pathogen and its copies must exit the nucleus in search of new cells to infect.

“Viral egress is crucial to the progress of the infection. That’s why we call it the most infectious stage of the virus’s lifecycle,” Wiggers said. “Many viruses manage to escape through the pores of the nucleus, but HSV-1 cannot do that because it’s too big.”

Nuclear pores have diameters of 39-40 nanometers, whereas HSV-1’s diameter is about 120 nm, Wiggers explained. A nanometer is a billionth of a meter.

In the first article, published in Cell in November, Grünewald’s group describes the step-by-step formation of the protein complex that helps HSV-1 to escape from the cell nucleus, known as the nuclear egress complex (NEC).

The second article, published in December, describes the NEC’s crystal structure, knowledge of which is fundamental to the development of inhibitors.

“The structure of these two proteins is most unusual,” Wiggers said. “It doesn’t fit any of the existing classifications.”

The disease

Generally speaking, HSV-1 is associated mainly with oral herpes and HSV-2 with genital herpes. In both cases, infection is typically recurrent, i.e., it comes and goes spontaneously. This is because the virus hides inside cells of the nervous system, hindering its elimination by the immune system.

Relapses usually occur at times of low immunity, which may be due to intense exposure to sunshine, emotional stress, menstruation or trauma.

One in five adults carries HSV-2, and more than half of the population has HSV-1. However, many carriers have no symptoms.

The article “Structural Basis of Vesicle Formation at the Inner Nuclear Membrane” (doi: 10.1016/j.cell.2015.11.029) can be read at www.cell.com/cell/fulltext/S0092-8674(15)01548-2.

The article “Crystal Structure of the Herpesvirus Nuclear Egress Complex Provides Insights into Inner Nuclear Membrane Remodeling” (doi: 10.1016/j.celrep.2015.11.008) can be read at www.cell.com/action/showImagesData?pii=S2211-1247%2815%2901295-4.