Abstract
BackgroundHuman immunodeficiency virus type 1 (HIV-1) must take advantage of its own proteins with two or more functions to successfully replicate. Although many attempts have been made to determine the function of viral proteins encoded in the HIV-1 genome, the role of the p2 peptide, a spacer between the capsid and the nucleocapsid in HIV-1 Gag in early-phase HIV infection still remains unclarified.ResultsIn this study, we show that the p2 peptide enhances HIV-1 acute infection by increasing intracellular ATP production via the activation of mitochondrial cytochrome c oxidase (MT-CO) involved in the respiratory chain. We found that cell-permeable p2-peptide-treated cells were more effectively infected by HIV-1 than control cells. To characterize the effect of the p2 peptide on HIV-1 replication in MAGIC-5 cells, various HIV-1 cDNA products were measured by quantitative real-time PCR. The levels of the late (R/gag), 2-LTR circular (2-LTR), and integrated (Alu) forms of viral cDNAs increased in the presence of the p2 peptide. Interestingly, yeast two-hybrid analysis revealed a novel interaction between the p2 peptide and the mitochondrial intermembrane space domain (N214–F235) of MT-CO subunit I (MT-CO1). Mutational analysis indicated that Gln6 in the p2 peptide is important for the interaction with MT-CO1. The p2 peptide activated MT-CO1 in vitro in a concentration-dependent manner, and fluorescence-microscopy analysis demonstrated that the p2 peptide had a significant effect on mitochondrial targeting. Furthermore, the analysis of HIV-1 lacking a functional p2 peptide demonstrated the inhibition of intracellular ATP production in MT-4 cells and monocyte-derived macrophages (MDMs) and a decrease in reverse transcription efficiency following infection of MT-4 cells and MDMs.ConclusionsThese findings provide evidence that the p2 peptide is a viral positive allosteric modulator of MT-CO and the increased intracellular ATP production after HIV infection in a p2-peptide-dependent manner is essential for efficient reverse transcription in early-phase HIV-1 infection.
Highlights
Human immunodeficiency virus type 1 (HIV-1) must take advantage of its own proteins with two or more functions to successfully replicate
We demonstrated that the p2 peptide released into the cytoplasm during HIV uncoating following the viral entry is targeted towards the mitochondrial intermembrane space domain (N214–F245) of MT-CO subunit I (MT-CO1) involved in the respiratory chain and increases mitochondrial cytochrome c oxidase (MT-CO) activity
The results indicated that the increase in HIV-1JRFL infectivity is dependent on the concentration of the Tat-p2 peptide (Fig. 1a)
Summary
Human immunodeficiency virus type 1 (HIV-1) must take advantage of its own proteins with two or more functions to successfully replicate. Many attempts have been made to determine the function of viral proteins encoded in the HIV-1 genome, the role of the p2 peptide, a spacer between the capsid and the nucleocapsid in HIV-1 Gag in early-phase HIV infection still remains unclarified. Some studies demonstrated that the p2 peptide functions in the late phase of the HIV-1 life cycle. Pettit et al reported that the p2 domain of the HIV-1 Gag precursor regulates sequential proteolytic processing and ensures the correct assembly of the virion [7]. Our previous study suggests that the p2 peptide is an inherent suicidal inhibitor of HIV-1 protease, because the p2 peptide inhibits the proteolytic cleavage of the recombinant Gag precursor protein into functional structural units [matrix (MA) and CA proteins] in vitro [8]. The virological function of the p2 peptide still remains unknown in the early phase of the viral life cycle
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