HIV-1 Tat amino acid residues that influence Tat-TAR binding affinity: a scoping review

HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is influenced by several factors including the HIV-1 subtype. HIV-1 subtype variation extends to sequence variation in the amino acids of the HIV-1 viral proteins. Of particular interest is the transactivation of transcription (Tat) protein due to its key function in viral transcription. The Tat protein predominantly functions by binding to the transactivation response (TAR) RNA element to activate HIV-1 transcriptional elongation. Subtype-specific Tat protein sequence variation influences Tat-TAR binding affinity. Despite several studies investigating Tat-TAR binding, it is not clear which regions of the Tat protein and/or individual Tat amino acid residues may contribute to TAR binding affinity. We, therefore, conducted a scoping review on studies investigating Tat-TAR binding. We aimed to synthesize the published data to determine (1) the regions of the Tat protein that may be involved in TAR binding, (2) key Tat amino acids involved in TAR binding and (3) if Tat subtype-specific variation influences TAR binding. A total of thirteen studies met our inclusion criteria and the key findings were that (1) both N-terminal and C-terminal amino acids outside the basic domain (47-59) may be important in increasing Tat-TAR binding affinity, (2) substitution of the amino acids Lysine and Arginine (47-59) resulted in a reduction in binding affinity to TAR, and (3) none of the included studies have investigated Tat subtype-specific substitutions and therefore no commentary could be made regarding which subtype may have a higher Tat-TAR binding affinity. Future studies investigating Tat-TAR binding should therefore use full-length Tat proteins and compare subtype-specific variations. Studies of such a nature may help explain why we see differential pathogenesis and prevalence when comparing HIV-1 subtypes.

Automated summary

HIV-1, a global health concern, exhibits complexity in its pathogenesis and prevalence due to factors including subtype variation. Subtype-specific sequence variation in the Tat protein influences Tat-TAR binding affinity, but the specific regions and amino acids involved are unclear. This scoping review synthesized 13 studies on Tat-TAR binding and found that both N-terminal and C-terminal amino acids outside the basic domain may play a role in increasing Tat-TAR binding affinity, substitutions of Lysine and Arginine in the basic domain reduced binding affinity, and subtype-specific variation of Tat has not been investigated. Future studies should use full-length Tat proteins and explore subtype-specific variations to better understand the differential pathogenesis and prevalence among HIV-1 subtypes.