Effect of HIV-1 subtype-specific Tat protein polymorphisms on Tat-TAR interaction

Alnara Zhamalbekova, Mahmoud A. A. Ibrahim, Peter A. Sidhom, Syed Hani Abidi

PLoS ONE, 2026

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DOI 10.1371/journal.pone.0346629
Data confidence 70 medium
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Abstract

INTRODUCTION: HIV Tat protein is responsible for HIV replication activation and interacts with the TAR RNA element for its function. Genetic polymorphisms in the Tat protein sequence can affect its interaction with the TAR element. Previous studies focusing on HIV subtypes B and C found that substitutions such as C31S, R57S, and Q63E can alter the binding conformations of the Tat protein and TAR element. However, it is not known if polymorphisms in other HIV subtypes can also affect Tat-TAR interactions. This study, therefore, aims to identify subtype-specific polymorphisms in the Tat protein and their effects on Tat-TAR interactions. METHODS: HIV Tat protein sequences from subtypes A, A1, A3, A6, B, C, D, CRF01_AE, and CRF02_A were retrieved from the HIV Los Alamos Database. The sequences were aligned and used to generate consensus sequences, which were subsequently used to identify subtype-specific Tat protein polymorphisms. The sequences were used to generate 3D models of the Tat protein using AlphaFold2, which were then used in molecular docking and molecular dynamics simulations over 200 ns using HDOCK and AMBER20, respectively, to identify the effects of subtype-specific polymorphisms on binding affinity and interaction with the TAR element. RESULTS: Our results show that subtypes A6, C, and CRF02_AG have higher affinity for TAR (with binding energies of -126.8, -123.2, and -123.3 kcal/mol, respectively). On the contrary, subtypes A3 and A1 had the weakest binding affinity to TAR, with binding energies of -63.3 and -57.5 kcal/mol, respectively. The increased and decreased affinity of Tat protein towards the TAR element may be attributed to subtype-specific polymorphisms (A3: K29A and R53K, A1: R57G, A6: K53R, Q54H, and V69I, C: V69I, C31S, and 58A, CRF02_AG: N24K and N29K). CONCLUSION: The results of the study suggest that subtype-specific polymorphisms can affect Tat-TAR interactions, allowing certain subtypes to interact much more strongly with TAR. This finding may have implications for the subtype-specific disease pathogenesis mediated by the Tat protein.