The p24 capsid plays an important role in the replication of HIV, particularly in the reverse transcription and nuclear entry processes. The capsid protects the viral reverse transcription complex (RTC) from antiviral sensors of the host cells, and breaks apart to release the pre-integration complex (PIC) for integration. However, the precise timing of the uncoating is unclear. It’s generally accepted that HIV can initiate reverse transcription in intact viral capsids because the p24 hexamers can alternate between closed and open conformation, which opens up a tiny pore that allows nucleotides to get in and out. So the uncoating is likely to occur during or after reverse transcription. Some researchers speculate that the capsid is uncoated before the reverse transcription is finished. The reason is that the capsid is too small to accommodate the DNA product (however, the RNA template is hydrolyzed at the same time of reverse transcription, which means the volume of nucleic acids should remain the same), and double stranded DNA is more rigid than single stranded RNA. As the reverse transcription proceeds, the pressure builds up inside, which eventually ruptures the capsid. The rupture of the capsid also makes room for the reverse transcription to finish. So I come up with an interesting idea. If the uncoating of the capsid is mandatory for the completion of the reverse transcription, can we test it by using mutations or small molecules like lenacapavir to stabilize the capsid and prevent its rupture? If the reverse transcription is unable to finish inside intact capsids, the uncoating must occur before its completion.
Jacques, D., McEwan, W., Hilditch, L. et al. HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature 536, 349–353 (2016). doi.org/10.1038/nature19098
Zila, V., Müller, T. G., Müller, B., and Kräusslich, H.-G. (2021b). HIV-1 capsid is the key orchestrator of early viral replication. PLoS Pathog. 17:e1010109. doi: 10.1371/journal.ppat.1010109