A prominent characteristic of human immunodeficiency virus type 1 (HIV-1) is its high genetic variability, which generates diversity of the virus and often causes a serious problem of the emergence of drug-resistant mutants. Subtype B HIV-1 is dominant in advanced countries, and the mortality rate due to subtype B HIV-1 has been decreased during the past decade. In contrast, the number of patients with non-subtype B viruses is still increasing in developing countries. One of the reasons for the prevalence of non-subtype B viruses is lack of information about the biological and therapeutic differences between subtype B and non-subtype B viruses. M36I is the most frequently observed polymorphism in non-subtype B HIV-1 proteases. However, since the 36th residue is located at a non-active site of the protease and has no direct interaction with any ligands, the structural role of M36I remains unclear. Here, we performed molecular dynamics (MD) simulations of M36I protease in complex with nelfinavir and revealed the influence of the M36I mutation. The results show that M36I regulates the size of the binding cavity of the protease. The reason for the rare emergence of D30N variants in non-subtype B HIV-1 proteases was also clarified from our computational analysis.
Nelfinavir (NFV) is a currently available HIV-1 protease (PR) inhibitor. Patients in whom NFV treatment has failed predominantly carry D30N mutants of HIV-1 PRs if they have been infected with the subtype B virus. In contrast, N88S mutants of HIV-1 PRs predominantly emerge in patients in whom NFV treatment has failed and who carry the CRF01_AE virus. Both D30N and N88S confer resistance against NFV. However, it remains unclear why the nonactive site mutation N88S confers resistance against NFV. In this study, we examined the resistance mechanism through computational simulations. The simulations suggested that despite the nonactive site mutation, N88S causes NFV resistance by reducing interactions between PR and NFV. We also investigated why the emergence rates of D30N and N88S differ between subtype B and CRF01_AE HIV-1. The simulations suggested that polymorphisms of CRF01_AE PR are involved in the emergence rate of the drug-resistant mutants.
HIV-1 has a large genetic diversity. Subtype B HIV-1 is commonly found in patients in developed countries. In contrast, an increasing number of patients are infected with the non-B subtype viruses, especially with subtype C HIV-1, in developing countries. It remains to be clarified how mutations or polymorphisms in non-B subtype HIV-1 influence the efficacy of the approved inhibitors. In this study, we have performed molecular dynamics simulations on clinically isolated subtype C HIV-1 proteases in complex with three kinds of approved inhibitors. From the structural and energetic viewpoints, we identified the polymorphisms influencing on the binding of the inhibitors. The effect of the V82I mutation on the association with chemicals and the reason for rare appearance of the D30N mutation in subtype C HIV-1 were discussed in terms of the change of geometry of the residues in HIV-1 protease.
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