Abstract
HIV-2 infection is frequently neglected in HIV/AIDS campaigns. However, a special emphasis must be given to HIV-2 as an untreated infection that also leads to AIDS and death, and for which the efficacy of most available drugs is limited against HIV-2. HIV envelope glycoproteins mediate binding to the receptor CD4 and co-receptors at the surface of the target cell, enabling fusion with the cell membrane and viral entry. Here, we developed and optimized a computer-assisted drug design approach of an important HIV-2 glycoprotein that allows us to explore and gain further insights at the molecular level into protein structures and interactions crucial for the inhibition of HIV-2 cell entry. The 3D structure of a key HIV-2ROD gp125 region was generated by a homology modeling campaign. To disclose the importance of the main structural features and compare them with experimental results, 3D-models of six mutants were also generated. These mutations revealed the selective impact on the behavior of the protein. Furthermore, molecular dynamics simulations were performed to optimize the models, and the dynamic behavior was tackled to account for structure flexibility and interactions network formation. Structurally, the mutations studied lead to a loss of aromatic features, which is very important for the establishment of π-π interactions and could induce a structural preference by a specific coreceptor. These new insights into the structure-function relationship of HIV-2 gp125 V3 and surrounding regions will help in the design of better models and the design of new small molecules capable to inhibit the attachment and binding of HIV with host cells.
Highlights
IntroductionAIDS (acquired immune deficiency syndrome) was discovered more than forty years ago, until now there is still no vaccine or cure for this disease
AIDS was discovered more than forty years ago, until now there is still no vaccine or cure for this disease
To obtain the 3D structures of human immunodeficiency virus (HIV)-2ROD wild-type and mutant isolates, a homo a broader knowledge of HIV-2 can be valuable to provide insight into the immune response modeling campaign was combining the analogous gp120ofglycoprote against HIV-1
Summary
AIDS (acquired immune deficiency syndrome) was discovered more than forty years ago, until now there is still no vaccine or cure for this disease. AIDS is caused by two human immunodeficiency virus (HIV) types, HIV-1 and HIV-2. HIV-1 is pandemic while HIV-2 is mainly confined to West Africa and western European countries (e.g., France, and Portugal). In areas where HIV-2 is endemic, co-infection with HIV-1 is very common [1]. Like HIV-1, HIV-2 is transmitted through direct contact with HIV-infected body fluids (blood, semen, and vaginal fluids) or from mother to newborns during pregnancy, delivery, or breastfeeding [2]. As the disease progresses, people infected with HIV-2 will become vulnerable to the same spectrum of associated opportunistic infections and co-morbidities as people infected with
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