Abstract
Human immunodeficiency virus type 1 (HIV-1) Tat is a virus-encoded trans-activator that plays a central role in viral transcription. We used our recently developed parallel analysis of in vitro translated open reading frames (ORFs) (PLATO) approach to identify host proteins that associate with HIV-1 Tat. From this proteomic assay, we identify 89 Tat-associated proteins (TAPs). We combine our results with other datasets of Tat or long terminal repeat (LTR)-associated proteins. For some of these proteins (NAT10, TINP1, XRCC5, SIN3A), we confirm their strong association with Tat. These TAPs also suppress Tat-mediated HIV-1 transcription. Removing suppression of HIV-1 transcription benefits the reversal of post-integrated, latent HIV-1 proviruses. We demonstrate that these transcriptionally suppressing TAPs contribute to HIV-1 latency in Jurkat latency (J-LAT) cells. Therefore, our proteomic analysis highlights the previously unappreciated TAPs that play a role in maintaining HIV-1 latency and can be further studied as potential pharmacological targets for the “shock and kill” HIV-1 cure strategy.
Highlights
Tat is a virus-encoded regulatory protein that is essential for human immunodeficiency virus type 1 (HIV-1) replication
We carried out the in vitro transcription/translation of host cellular proteins from a human ORFeome library. This allowed for the formation of mRNA/protein/ribosome complexes that were incubated with glutathione beads carrying immobilized glutathione S-transferase (GST)-Tat or GST alone as a control (Figure S1)
Following mRNA elution and deep sequencing analysis, we identified 89 Tat-associated proteins (TAPs) (Figure 1B)
Summary
Tat is a virus-encoded regulatory protein that is essential for human immunodeficiency virus type 1 (HIV-1) replication. Tat possesses multiple functions, it is primarily involved in the transcription of integrated HIV-1 proviruses. Once the host cellular transcription factors nuclear factor kappa B (NF-κB) and Nuclear factor of activated T-cells 1 (NFAT1) bind to the enhancer region of the HIV-1 5’ long terminal repeat (LTR) promoter, they recruit histone acetyltransferase (HAT) to acetylate histones and stimulate viral gene expression. Tat protein is produced, which induces a positive feedback loop to amplify HIV-1 transcription. Tat associates with the RNA polymerase II (Pol II) pre-initiation complex (PIC), and plays a role in both initiation and elongation [1]. Tat increases PIC formation on HIV-1 5’ LTRs and stabilizes the complex during elongation [1,2]
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