The HIV-1 gag p6: a promising target for therapeutic intervention

Abstract

The p6 domain of the Gag precursors (Gag p6) in human immunodeficiency virus type 1 (HIV-1) plays multifunctional roles in the viral life cycle. It utilizes the endosomal sorting complex required for transport (ESCRT) system to facilitate viral budding and release from the plasma membrane through the interactions with the ESCRT-I component tumor susceptibility gene 101 (TSG101) and with the ALG-2 interacting protein X (ALIX). Moreover, Gag p6 contributes to viral replication by a range of posttranslational modifications such as SUMOylation, ubiquitination and phosphorylation. Additionally, Gag p6 also mediates the incorporation of the accessory protein Vpr into virions, thereby promoting Vpr-induced viral replication. However, less attention is focused on Gag p6 as therapeutic intervention. This review focuses on the structures and diverse functions of Gag p6 in viral replication, host cells, and pathogenesis. Additionally, several challenges were also discussed in studying the structure of Gag p6 and its interactions with partners. Consequently, it concludes that the Gag p6 represents an attractive target for the development of antiretroviral drugs, and efforts to develop p6-targeted antiretrovirals are expected to undergo significant growth in the forthcoming years.

Keywords: Antiretrovirals; HIV-1 Gag p6; Viral replication and budding.

Fig. 1

Structures of HIV-1 p6 in different solutions. Solution structures of HIV-1 p6 (A) in a distilled trifluoroethanol-d₂ (TFE-d₂)/H₂O environment (PDB: 2C55) and (B) in the presence of dodecylphosphocholine (DPC) micelles (PDB: 7P3O). (C) Superposition of two structures

Fig. 2

Functional sites of HIV-1 Gag p6, process of viral budding, and Vpr multifunction in the newly infected cells. (A) Summary of the primary sequence and important functional sites in HIV-1 Gag p6. Two α -helices, H1 and H2, are represented by the light green bars. The binding domains for tumor susceptibility gene 101 (TSG101), ALG-2 interacting protein X (ALIX) and Vpr visually portrayed in dark blue, red, and purple, respectively. Phosphorylation sites are indicated by orange spheres. The attachment sites for ubiquitin (Ub) are depicted as light green spheres, while the attachments sites for small ubiquitin-like modifier 1 (SUMO-1) are designated by light blue spheres. The grey spheres correspond to the glutamic acids that contribute to viral replication. (B) HIV-1 budding process facilitated by Gag p6 and viral replication promoted by Vpr. The Gag p6 recruits endosomal sorting complex required for transport (ESCRT) to facilitate membrane scission and particle release. In subsequent infections, Vpr performs various functions, including promoting the reverse-transcription process, facilitating the nuclear import of the pre-integration complex, inducing cell cycle arrest and apoptosis, transactivating the HIV-LTR, and counteracting host restriction factors