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

School of Biotechnology and Bioinformatics, D Y Patil Deemed to be University, Plot 50, Sector 15, CBD Belapur, Navi Mumbai, Maharashtra 400614, India
Research and Development, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
Author to whom correspondence should be addressed.
Med. Sci. 2019, 7(6), 74;
Received: 21 May 2019 / Revised: 15 June 2019 / Accepted: 19 June 2019 / Published: 22 June 2019
(This article belongs to the Special Issue NeuroAIDS: Cognition, Immunology, Virology and Drug Abuse)
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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. View Full-Text
Keywords: HIV-1 Vpu; tetherin; transmembrane interactions; aggregation potential HIV-1 Vpu; tetherin; transmembrane interactions; aggregation potential

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Sneha, P.; Shah, U.; Balaji, S. In Silico Insights into HIV-1 Vpu-Tetherin Interactions and Its Mutational Counterparts. Med. Sci. 2019, 7, 74.

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