Over millions of years cells have evolved to be very good at protecting themselves from infection. On the other hand viruses have evolved to infect their host, bypassing immune defenses. The protective intracellular innate immune system depends on detection of infection: pattern recognition receptors recognize pathogen associated molecular patterns. Defence also depends on suppression: restriction factors, induced by pattern recognition, inhibit viral functions. Our goal is to understand how viruses evade or antagonize intracellular innate immunity to allow infection and replication. We focus on HIV. We find that cytoplasmic DNA sensing is a problem for retroviruses because they make DNA in the cytoplasm. We hypothesized that HIV carries out DNA synthesis within its capsid, regulated by cofactors, in a process we call cloaking. This opposes textbook dogma, which states early capsid uncoating prior to DNA synthesis. Investigating this hypothesis led to our discovery that the HIV-1 core contains electrostatic channels which transport nucleotides and fuel encapsidated DNA synthesis. We find that poorly transmissible HIV strains are far less effective at evasion of DNA sensing, perhaps explaining their failure to reach pandemic levels of human-to-human spread. This developing understanding of how HIV evades innate sensing and the consequences of activating sensing allows us to develop drugs with broad specificity that uncloak viral infection. We have also discovered that some of the most effective anti-HIV drugs already do this, disturbing cloaking and activating innate immunity in infected cells. These observations underline the importance of studying the relationship between viral infection and innate immunity and illustrate its translational potential.
About the lecture series:
Adam Neville as the Principal of the University of Dundee from 1978-1987. This lecture series was set up in recognition of Adam Neville’s key role in ensuring the survival of the Department of Biochemistry in the late 1970s at a time when its financial position was extremely precarious. This is one of SLS’s most prestigious named lectures.
The talk will be followed by a refreshments in WTB Life Space, to which everyone is invited.