Our observation that pandemic HIV effectively evades innate immune sensing might be generalizable to other pandemic viruses. We wonder whether we can determine which viruses are most likely to become pandemic by assessing their capacity to evade human sensing. For example, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Alpha variant, which became dominant in late 2020, has adapted to enhance its innate immune evasion3.

A roadblock in our understanding of the HIV capsid is that the mechanism by which capsid adaptation alters visibility to cGAS and TRIM5 remains poorly understood. We hypothesize that evasion of cytoplasmic DNA sensor cGAS depends on keeping the viral DNA safe inside the capsid until release in the nucleus. But how capsid adaptation regulates uncoating and how TRIM5 sensitivity is altered remain unclear. Recruitment of the host factor cyclophilin A by the capsid has a role in regulation of uncoating and TRIM5 recruitment4, but whether cyclophilin A is changing capsid dynamics or conformation, or simply obstructing TRIM5 binding, remains unclear.

Improved understanding of how the capsid functions and adapts to its new host on zoonosis will depend on studying larger complexes of capsid proteins, ideally whole cone-shaped cores and their interactions with recombinant cofactors. Cryo-electron microscopy studies are likely to provide the biggest breakthroughs in our understanding of HIV capsid function in the near future, and we look forward to contributing to those studies.

Greg J. Towers 1and Lorena Zuliani-Alvarez 2

1UCL, London, UK.

2UCSF, San Francisco, CA, USA.