The HIV-1 capsid is involved in several processes during the early stages of infection. Through the engagement of cofactors CypA and CPSF6 it protects the newly synthesized viral DNA from detection by host sensors and nucleases. Similarly, through binding of the nuclear pore complex (specifically Nup358 and Nup153) the capsid also plays a key role in nuclear import of the pre-integration complex. Several lines of inquiry support a model in which reverse transcription takes place within the capsid. In particular, the observation that assembled CA hexamers are required to engage Nup153 demonstrates that the capsid remains intact at least until it reaches the nuclear pore complex.
If reverse transcription can take place within the capsid interior, then the capsid itself must allow entry of substrate dNTP’s. Using comparative structural analyses along with various biophysical methods we have been able to show that the capsid contains a structurally dynamic pore that is capable of recruiting dNTP’s with nanomolar affinities and with diffusion-limited kinetics. Off-rate measurements also indicate that dNTP’s can rapidly dissociate from the pore. This combination of high affinity and fast off-rate is ideal for a selective pore as it effectively acts to concentrate dNTP’s at the site of the reverse transcription reaction while avoiding inhibition through tight sequestration. The electrostatic nature of the pore is highly conserved between lentiviruses, but is thermodynamically destabilising to the capsid lattice. The combination of conservation and strain is a hallmark of active sites and is consistent with a feature that is tolerated because it provides a benefit to the virus.
These observations add another dimension to our understanding of the HIV-1 capsid, which until recently had been regarded as a passive player in the virus life cycle.