Cells are very hostile places for viruses. The intracellular innate immune system typically protects cells from infection and successful viruses must evade, avoid or antagonise innate immune defenses in order to infect their host. The host-virus interactions involved in innate evasion dictate species and cell type specific replication. A key feature of innate immune sensing is detection of foreign nucleic acids. For example, cytoplasmic DNA is sensed as a danger signal leading to production of inflammatory cytokines and cell death. Our central research question is: How do retroviruses infect cells without activating innate immune defenses when they synthesise viral DNA in the
cytoplasm? We hypothesise that HIV DNA synthesis is contained within the protective shell of the viral capsid, which protects it from nucleases and DNA sensors, in a process we call cloaking. We have discovered that the capsid hexamers form channels through which we propose nucleotides are transported to fuel encapsidated DNA synthesis. We find that breaking cofactor interactions by depleting cofactors, or by mutation of CA cofactor binding sites, causes virus to trigger innate immune sensors and suppresses replication in innate immune competent cells. We have also compared the capsids of pandemic HIV isolates and their less successful non-pandemic counterparts. We find that non-pandemic HIV are much less effective at innate evasion and have quite different capsid structures. We propose that adapting to evade innate sensing in myeloid cells is a key feature driving HIV-1 pandemicity. We have used this new knowledge to develop capsid and host cofactor-targeting inhibitors, which uncloak virus and cause innate immune activation, as a novel paradigm for prophylaxis and treatment of viral infection.