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

Abstract

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.

Keywords: Molecular binding; Subtype variation; Tat polymorphism; Transactivation of transcription; Transactivation response RNA element.

Fig. 1

3D predicted structure of the HIV-1 subtype B Tat protein (subtype B, Isolate MN) (1–86) using Swiss-model webserver. The alpha-helical structure is coloured red and the N and C- terminals are yellow coloured

Fig. 2

Multiple sequence alignment of various HIV-1 Tat subtypes. From top to bottom; Tat subtype H (isolate 90CF056), subtype D (isolate ELI), subtype G (isolate SE6165), subtype B (isolate MN), subtype K (isolate 96CM-MP535), subtype A (isolate U455), subtype J (isolate SE9280) and subtype C (isolate 92BR025). Tat protein is encoded by two exons, exon one spans the region of amino acids 1–72 and exon two spans the region of 73–101. The Tat protein is made up of six function regions including the proline-rich region (1–21), the cysteine-rich region (22–37), the core region (38–48), the basic, arginine-rich domain (49–59), the glutamine-rich domain (60–72) and the RGD domain (73–101). The black arrows indicate the two exons

Fig. 3

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for results of the search strategy