During my PhD I spent many an hour in a dark room, staring down a microscope, manually counting cells infected with hepatitis C virus (see my earlier post). As I robotically clicked away at the tally counter my thoughts would often stray; after the inevitable plans for what I would eat for dinner, I would start thinking about the microscopic events that had led to the pattern of infection I could see through the eyepiece.
Each group of infected cells that I counted had arisen from a single virus particle infecting a single cell. But I was curious: how many viruses took part in the experiment, how many attached to any given cell, how many succeeded in entering a cell? It occurred to me that the whole process was likely to be probabilisitic; there are multiple steps a virus particle has to take towards productive infection and it was possible that the majority of virus particles fail at some stage and fall by the wayside. It also occurred to me that to investigate this would require some maths, alas, I am no Carl Friedrich Gauss. My thoughts went no further.
Seven years pass, I am at virology meeting having presented some of our work on virus entry. Over breakfast Chris Illingworth enquires "have you ever considered mathematical modelling of virus entry". By comparison to me, Chris is Carl Friedrich Gauss. We collaborated over the course of 18 months to design experiments and build a mathematical framework to understand the early stages of virus entry by hepatitis C virus. The products of this work have just been uploaded to bioRxiv (and submitted for publication, watch this space...).
Working with Chris has proven to be very rewarding. We were able to start with data generated by basic virology assays, build a mechanistic framework to explain that data and then use mathematical modelling to test that framework and make new predictions. I won't provide great detail in this post (you can read it for yourself), however, I can start to answer some of the questions posed by my younger self: our work suggests that HCV entry is extremely inefficient, of the virus particles that manage to attach to the cell surface only ~25% make it past the early stages of virus entry, of these, only ~5% make it to productive infection. This discovery may explain the, so-called, 'bottleneck' in HCV transmission between people; sequencing data indicates that only a 1-4 particles are responsible for establishing new infections.
On another matter, the molecular events of HCV entry are targeted by potent neutralising antibodies. We are hoping that our mechanistic model will help us to better understand how HCV evades these antibodies.