Analysis of the effect of HIV-1 subtype-specific Tat polymorphisms on Tat-TAR interaction

Abstract Introduction: HIV Tat is responsible for HIV replication activation and interacts with the TAR RNA element for its function. Genetic polymorphisms in the Tat sequence can affect the interaction between Tat and TAR. Previous studies, focusing on HIV subtypes B and C, found that substitutions such as C31S, R57S, and Q63E can alter the binding conformations of Tat and TAR. 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 TAR and their effect on Tat-TAR interactions. Methods: HIV Tat sequences from subtypes A, A1, A2, A3, A4, A6, A7, A8, B, C, D, CRF01_AE, and CRF02_AG was retrieved from the HIV Los Alamos Database. The sequences were aligned and used to generate consensus sequences, subsequently to identify subtype-specific Tat polymorphisms. The sequences were used to generate 3D models of Tat, which were used in molecular docking and molecular dynamic simulations analyses (performed using HDOCK and Desmond tools, respectively) to identify the effect of subtype-specific polymorphisms on binding affinity and interaction with TAR element. Results: Our results show that subtypes A7, A2, and D showed higher affinity to TAR (with a docking score range of -171.36 to -231.79 and free energy binding range of -111.66 to -123.94 kJ/mol). The subtype-specific polymorphisms that may have increased affinity were Lysine 29 (K29) and Proline 36 (P36). On the contrary, subtype A3 had the weakest binding affinity to TAR with a docking score of -177.78 and free energy of binding value of -54.15 kJ/mol. This lowered affinity may be attributed to subtype-specific polymorphisms such as Alanine 29 (29A) and Proline 59 (59P). 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 as compared to others. This finding may have implications in the subtype-specific disease pathogenesis mediated by the Tat protein.