In Silico Insights into HIV-1 Vpu-Tetherin Interactions and Its Mutational Counterparts.

Patil Sneha,Seetharaman Balaji,Urmi Shah

doi:10.3390/medsci7060074

Abstract

Tetherin, an interferon-induced host protein encoded by the bone marrow stromal antigen 2 (BST2/CD317/HM1.24) gene, is involved in obstructing the release of many retroviruses and other enveloped viruses by cross-linking the budding virus particles to the cell surface. This activity is antagonized in the case of human immunodeficiency virus (HIV)-1 wherein its accessory protein Viral Protein U (Vpu) interacts with tetherin, causing its downregulation from the cell surface. Vpu and tetherin connect through their transmembrane (TM) domains, culminating into events leading to tetherin degradation by recruitment of β-TrCP2. However, mutations in the TM domains of both proteins are reported to act as a resistance mechanism to Vpu countermeasure impacting tetherin’s sensitivity towards Vpu but retaining its antiviral activity. Our study illustrates the binding aspects of blood-derived, brain-derived, and consensus HIV-1 Vpu with tetherin through protein–protein docking. The analysis of the bound complexes confirms the blood-derived Vpu–tetherin complex to have the best binding affinity as compared to other two. The mutations in tetherin and Vpu are devised computationally and are subjected to protein–protein interactions. The complexes are tested for their binding affinities, residue connections, hydrophobic forces, and, finally, the effect of mutation on their interactions. The single point mutations in tetherin at positions L23Y, L24T, and P40T, and triple mutations at {L22S, F44Y, L37I} and {L23T, L37T, T45I}, while single point mutations in Vpu at positions A19H and W23Y and triplet of mutations at {V10K, A11L, A19T}, {V14T, I18T, I26S}, and {A11T, V14L, A15T} have revealed no polar contacts with minimal hydrophobic interactions between Vpu and tetherin, resulting in reduced binding affinity. Additionally, we have explored the aggregation potential of tetherin and its association with the brain-derived Vpu protein. This work is a possible step toward an understanding of Vpu–tetherin interactions.

Highlights

Tetherin, a protein encoded by the BST2 gene, known as bone marrow stromal antigen2/ CD317/HM1.24, is an integral membrane protein involved in the interferon dependent antiviral response pathway [1]
The Ramachandran plot statistics of the modeled Viral Protein U (Vpu) structures presented in Table 3 had over 90% of residues in the most favorable region, indicating good overall model quality
The host immune responses may be attributed to the variability wherein polymorphism is acquired the Vpu–tetherin interactions studied here have considered the human immunodeficiency virus (HIV)-1 Vpu sequences from both blood as a means of immune escape or other functional benefit [21]

Summary

Introduction

A protein encoded by the BST2 gene, known as bone marrow stromal antigen. 2/ CD317/HM1.24, is an integral membrane protein involved in the interferon dependent antiviral response pathway [1]. The antiviral activity of tetherin is bestowed upon by its unique topology that blocks the budding viruses and prevents them from leaving the cell [2]. Its N-terminal region is in the cytoplasm with a membrane spanning the helical domain (transmembrane (TM) domain) and an alpha helical coiled coil ectodomain with a glycosyl-phosphatidylinositol modified anchor at C-terminal [3,4]. Tetherin serves as a potent inhibitor of enveloped viruses, like human immunodeficiency virus (HIV), Med. Sci. 2019, 7, 74 by its tethering phenomena, eventually leading to lysosomal degradation of tethered viral particles [5] Sci. 2019, 7, 74 by its tethering phenomena, eventually leading to lysosomal degradation of tethered viral particles [5]

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Discussion

Conclusion