Abstract
Gag, as the major structural protein of HIV-1, is necessary for the assembly of the HIV-1 sphere shell. An in-depth understanding of its trafficking and polymerization is important for gaining further insights into the mechanisms of HIV-1 replication and the design of antiviral drugs. We developed a mathematical model to simulate two biophysical processes, specifically Gag monomer and dimer transport in the cytoplasm and the polymerization of monomers to form a hexamer underneath the plasma membrane. Using experimental data, an optimization approach was utilized to identify the model parameters, and the identifiability and sensitivity of these parameters were then analyzed. Using our model, we analyzed the weight of the pathways involved in the polymerization reactions and concluded that the predominant pathways for the formation of a hexamer might be the polymerization of two monomers to form a dimer, the polymerization of a dimer and a monomer to form a trimer, and the polymerization of two trimers to form a hexamer. We then deduced that the dimer and trimer intermediates might be crucial in hexamer formation. We also explored four theoretical combined methods for Gag suppression, and hypothesized that the N-terminal glycine residue of the MA domain of Gag might be a promising drug target. This work serves as a guide for future theoretical and experimental efforts aiming to understand HIV-1 Gag trafficking and polymerization, and might help accelerate the efficiency of anti-AIDS drug design.
Highlights
Gag protein (Gag) is the major structural polyprotein of HIV-1 and is synthesized in large amounts in the cytoplasm
An in-depth understanding of Gag protein trafficking and polymerization is important for gaining further insights into the mechanisms of HIV-1 replication and the design of antiviral drugs
Optimization and quantitative analysis, we hypothesized the budding and release time of virus-like particles and revealed that the dimer and trimer intermediates might be crucial in hexamer formation
Summary
Gag protein (Gag) is the major structural polyprotein of HIV-1 and is synthesized in large amounts in the cytoplasm. Gag diffuses freely within the cytoplasm, hijacks the molecular motors, and moves along microtubules to the cytosolic side of the plasma membrane (PM) domain [1, 2]. Underneath the PM, the immature HIV-1 Gag shell assembles in a radial arrangement. Gag is composed of six constitutive components: the N-terminal matrix (MA) domain, the capsid (CA) domain, the first spacer peptide (SP1), the nucleocapsid (NC) domain, a second spacer peptide (SP2) and the p6 (p6) domain. During the phase of HIV-1 maturation, Gag disconnects from the MA and reassembles to form the cone-shaped viral core. Gag is necessary for HIV-1 replication, interfering with the trafficking and assembly of Gag has been a focus of research [3, 4]
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