Toll-Interacting Protein Suppresses HIV-1 Long-Terminal-Repeat-Driven Gene Expression and Silences the Post-Integrational Transcription of Viral Proviral DNA

• Published in: PloS one 2015-04, Vol.10 (4), p.e0125563-e0125563
• Main Authors: Yang, Fu-Chun, Kuang, Wen-Dong, Li, Chuan, Sun, Wei-Wei, Qu, Di, Wang, Jian-Hua
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; C-Terminus; Cells, Cultured; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - metabolism; Deoxyribonucleic acid; DNA; DNA, Viral - genetics; Gene expression; Genetic engineering; Glycoprotein gp120; Glycoproteins; Health aspects; HEK293 Cells; HeLa Cells; HIV; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - immunology; HIV Envelope Protein gp120 - metabolism; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - virology; HIV Long Terminal Repeat; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Immune system; Infection; Infections; Interleukin 1; Interleukin 1 receptors; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Latency; Long terminal repeat; Monocytes; Monocytes - cytology; Monocytes - immunology; Monocytes - virology; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Plasmids; Proteins; Signaling; Toll-like receptors; Transcription; Transcription (Genetics); Transcription, Genetic; Virus Integration; Virus replication
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125563

Toll-interacting protein (Tollip) is a host adaptor protein for negatively regulating Toll-like receptor 2-, 4-, and IL-1R (interleukin-1 receptor)-mediated signaling. We found that Tollip expression could be induced in MDDCs (monocyte-derived dendritic cells) by HIV-1 particles and recombinant gp120 glycoprotein. Hence, we investigated the role of Tollip in modulating HIV-1 infection. We found that Tollip expression suppressed NF-κB-dependent HIV-1 long terminal repeat (LTR)-driven transcription and thus inhibited HIV-1 infection. Our protein truncation experiments proved that the intact C-terminus of Tollip was required for inhibition of both NF-κB activity and HIV-1 LTR-driven gene expression. Intriguingly, Tollip silenced the post-integrational transcription of HIV-1 proviral DNA, indicating the potential role of Tollip in maintaining viral persistence. Our results reveal the novel role of host factor Tollip in modulating HIV-1 infection, and may suggest the hijacking of Tollip as the negative regulator of the TLR pathway and even the downstream signaling, by HIV-1 for maintaining persistent infection. Further elucidation of the mechanisms by which HIV-1 induces Tollip expression and identification of the role of Tollip in modulating HIV-1 latency will facilitate the understanding of host regulation in viral replication and benefit the exploration of novel strategies for combating HIV-1 infection.