The Role of Capsid in the Early Steps of HIV-1 Infection: New Insights into the Core of the Matter

Abstract

In recent years, major advances in research and experimental approaches have significantly increased our knowledge on the role of the HIV-1 capsid in the virus life cycle, from reverse transcription to integration and gene expression. This makes the capsid protein a good pharmacological target to inhibit HIV-1 replication. This review covers our current understanding of the role of the viral capsid in the HIV-1 life cycle and its interaction with different host factors that enable reverse transcription, trafficking towards the nucleus, nuclear import and integration into host chromosomes. It also describes different promising small molecules, some of them in clinical trials, as potential targets for HIV-1 therapy.

Keywords: HIV-1; capsid; drugs; integration; nuclear entry; reverse transcription.

Figure 1

Structure of HIV-1 capsid. (A) The structure of the CA monomer showing the N-terminal domain (NTD), the C-terminal domain and the CypA-binding loop (highlighted) (PDB 4XFY) [20]. (B) The structure of pentameric HIV-1 CA (PDB 3P05) [21]. (C) The structure of hexameric HIV-1 CA (PDB 4XFY) [20]. (D) The hexameric and pentameric subunits assemble into a fullerene conical capsid core (PDB 3J3Y). In this model, the core is composed of 186 hexamers and 12 pentamers [22].

Figure 2

IP₆ binds to CA hexamers. (A) IP₆ bound to the central channel of the immature capsid hexamer (PDB 6BHR) [29]. (B) IP₆ bound to the Arg18 ring in the central channel of the mature CA hexamer (PDB 6ES8) [28].

Figure 3

A model showing HIV-1 CA-interacting host factors during microtubule trafficking, nuclear import and integration targeting. Dynein adaptor protein BICD2 and kinesin-1 adaptor protein FEZ1 bind to HIV-1 CA and facilitate the HIV-1 reverse transcription complex (RTC)/pre-integration complex (PIC) trafficking towards the nuclear membrane. At the nuclear pore complex (NPC), Nup358 interacts with the CA protein and mediates the docking of RTC/PIC. Then, Nup153 interacts with the CA protein and mediates PIC translocation through the NPC. CPSF6 then binds to and directs CA to active regions of euchromatin, proximal to nuclear speckles and speckle-associated domains (SPADs). TNPO3 also facilitate virus integration, possibly by promoting nuclear core uncoating.