Abstract
Human immunodeficiency virus (HIV) is a global health concern affecting millions of individuals with a wide variety of currently circulating subtypes affecting various regions of the globe. HIV relies on multiple regulatory proteins to modify the host cell to promote replication in infected T cells, and these regulatory proteins can have subtle phenotypic differences between subtypes. One of these proteins, HIV-1 Trans-Activator of Transcription (Tat), is capable of RNA interference (RNAi) Silencing Suppressor (RSS) activity and induction of cell death in T cells. However, the subtype-specific RSS activity and induction of cell death have not been explored. We investigated the ability of Tat subtypes and variants to induce RSS activity and cell death. TatB, from HIV-1 subtype B, was found to be a potent RSS activator by 40% whereas TatC, from HIV-1 subtype C, showed 15% RSS activity while subtype TatC variants exhibited varying levels. A high level of cell death (50–53%) was induced by subtype TatB when compared to subtype TatC (25–28%) and varying levels were observed with subtype TatC variants. These differential activities could be due to variations in the functional domains of Tat. These observations further our understanding of subtype-specific augmentation of Tat in HIV-1 replication and pathogenesis.
Highlights
Among all the genetic human immunodeficiency virus (HIV) subtypes that exist in the world, subtype C is responsible for ~50% of Human immunodeficiency virus (HIV)-1 infections globally which included parts of Africa and Asia regions namely China, India etc., whereas in North America and Europe, the majority of HIV infectionsViruses 2019, 11, 976; doi:10.3390/v11110976 www.mdpi.com/journal/virusesViruses 2019, 11, 976 are caused by subtype B [1,2]
Tat is involved in RNA interference (RNAi) silencing suppressor (RSS) activity [20] and induction of cell death in T cells [21]
Tat is reported to act as suppressor of RNAi by binding to double-stranded RNA-specific endoribonuclease (DICER) (RNA-specific endoribonucleases), thereby causing RNAi suppression [27,52]
Summary
Among all the genetic human immunodeficiency virus (HIV) subtypes that exist in the world, subtype C is responsible for ~50% of HIV-1 infections globally which included parts of Africa and Asia regions namely China, India etc., whereas in North America and Europe, the majority of HIV infectionsViruses 2019, 11, 976; doi:10.3390/v11110976 www.mdpi.com/journal/virusesViruses 2019, 11, 976 are caused by subtype B [1,2]. Tat is a 12 kD major regulatory transcription protein, encoded by exon-1 (1–72 amino acids (aa)). Exon-2 (73–101 aa) of the Tat gene and it contributes to several pathological symptoms of HIV-1 infection and replication [9,10,11]. Tat binds to nascent leader RNA and augments the HIV-1 promoter for transcription of viral genes [12]. The trans-activation domain of Tat (1–48 aa) is implicated in interactions with several cellular proteins [15], namely CyclinT1, Sp1, Histone Acetyl Transferase (HAT) and Protein Kinase R (PKR), while the basic domain of Tat (49–72 aa) is involved in binding to TAR [16], nuclear localization [17] and plasma membrane permeability [18]. Tat is involved in RNAi silencing suppressor (RSS) activity [20] and induction of cell death in T cells [21]
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