Formation of the tRNALys packaging complex in HIV-1

Abstract

Human immunodeficiency virus 1 (HIV-1) uses a host cell tRNA(Lys,3) molecule to prime reverse transcription of the viral RNA genome into double-stranded DNA prior to integration into the host genome. All three human tRNA(Lys) isoacceptors along with human lysyl-tRNA synthetase (LysRS) are selectively packaged into HIV-1. Packaging of LysRS requires the viral Gag polyprotein and incorporation of tRNA(Lys) additionally requires the Gag-Pol precursor. A model that incorporates the known interactions between components of the putative packaging complex is presented. The molecular interactions that direct assembly of the tRNA(Lys)/LysRS packaging complex hold promise for the development of new anti-viral agents.

Figure 1

Cartoons showing the mature HIV-1 virion and HIV-1 lifecycle. (A) Schematic of the mature virus structure. MA is shown binding the virus membrane and CA forms the core, within which NC is bound to two copies of the viral genomic RNA. Inside the core, tRNA^Lys,3 is shown annealed to the genome. Whether free or tRNA-bound LysRS is found in the core is not known. (B) Scheme of HIV-1 life cycle adapted from [83]. Assembly is a complex process that occurs at the PM and results in budding and maturation of new virions. During assembly, LysRS and tRNALys are packaged by the Gag and Gag-Pol viral proteins.

Figure 1

Cartoons showing the mature HIV-1 virion and HIV-1 lifecycle. (A) Schematic of the mature virus structure. MA is shown binding the virus membrane and CA forms the core, within which NC is bound to two copies of the viral genomic RNA. Inside the core, tRNA^Lys,3 is shown annealed to the genome. Whether free or tRNA-bound LysRS is found in the core is not known. (B) Scheme of HIV-1 life cycle adapted from [83]. Assembly is a complex process that occurs at the PM and results in budding and maturation of new virions. During assembly, LysRS and tRNALys are packaged by the Gag and Gag-Pol viral proteins.

Figure 2

Schematic illustration of the interactions that may occur within the LysRS/tRNA^Lys packaging complex. A single copy of each molecule is shown for simplicity. The Gag protein interacts with LysRS via the CA C-terminal domain (CTD) and Pol interactions (RT domain) with LysRS have also been reported to play a role in vivo. The RT domain of Pol also interacts with tRNA^Lys and may help to position tRNA^Lys,3 for annealing onto the PBS. CA-CTD/CA-CTD interactions occur between Gag proteins and between Gag and Gag-Pol. The highly basic NC protein contacts the viral RNA packaging signal, and additional contacts between the viral RNA and LysRS may also occur. The RNA secondary structure proximal to the PBS is taken from [84].