Gag-Pol Processing during HIV-1 Virion Maturation: A Systems Biology Approach
Figure 2
The time course of simulated Gag and Gag-Pol processing.
Initial concentrations of Gag and Gag-Pol were set to reflect the quantities within a single virion; cleavage rates were parameterized according to in vitro estimates (Table 1). (A) Virus maturation time (VMT) as defined by the molecular species known to govern virion maturation: Morphological maturation (indicated by dashed red line in all panels) is triggered by the decay of the CA.SP1 fragment (blue line; threshold of trans-dominant inhibition of particle maturation indicated by dashed horizontal line) and is not limited by the availability of liberated CA molecules (green line; threshold of one capsid unit corresponding to 1,500 CA molecules per particle is indicated by solid horizontal line). (B) Generation of catalytically active intermediate dimeric forms containing PR. Full-length Gag-Pol (red line) dimerizes rapidly and N-terminal auto-cleavage gives rise to enzymatically active intermediate dimeric forms (black, blue and green lines). (C) Decay of Gag substrate (black line) and accumulation of final Gag cleavage products. (D) Accumulation of final Pol cleavage products. (E) Enzyme concentrations and related metrics. The ratio PRdPR/Etot indicates the relative contribution of mature PR dimers to the proteolytic activity. The ratio Etot/Stot of the total concentration of active enzyme forms and the total concentration of uncleaved cleavage sites stays below one throughout the simulated time course, which justifies the use of Michaelis-Menten kinetics. Etot – total proteolytic activity; Stot – all uncleaved cleavage sites; IEF – all active intermediate enzyme (PR) forms; RT: p51/p66 heterodimer. All other dimers are indicated in the form M1dM2, where M1,2 are the monomers.