HIV-1 Tat Interacts with a Kaposi’s Sarcoma-Associated Herpesvirus Reactivation-Upregulated Antiangiogenic Long Noncoding RNA, and Antagonizes Its Function

Kaposi’s sarcoma associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma (KS), an acquired immunodeficiency syndrome (AIDS)-defining 43 cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency viruses (HIV)-infected AIDS patients has been ascribed to HIV-1 45 and KSHV interaction, focusing on secretory proteins. HIV-1 secreted protein 46 HIV-Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. 47 However, the impact and underlying mechanisms of HIV-Tat in KSHV-infected 48 endothelial cells undergoing viral lytic reactivation remain unclear. Here, we 49 identified LINC00313 as a novel KSHV reactivation-activated long non-coding RNA 50 (lncRNA) that interacts with HIV-Tat. We found that LINC00313 overexpression 51 inhibits cell migration, invasion and tube formation, and this suppressive effect was 52 relieve by HIV-Tat. In addition, LINC00313 bound to polycomb repressive complex 2 53 (PRC2) complex components and this interaction was disrupted by HIV-Tat 54 suggesting that LINC00313 may mediate transcription repression through recruitment 55 of PRC2 and HIV-Tat alleviates repression through disruption of this association. This 56 notion was further supported by bioinformatics analysis of transcriptome profiles in 57 LINC00313 overexpression combined with HIV-Tat treatment. Ingenuity Pathway 58 Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell 59 movement and migration pathways, and enrichment of these pathways was absent in 60 the presence of HIV-Tat. Collectively, our results illustrate that an angiogenic 61 repressive lncRNA, LINC00313 that is up-regulated during KSHV reactivation 62 interacts with HIV-Tat to promote endothelial cell motility. These results demonstrate 63 that a lncRNA serves as a novel connector in HIV-KSHV Given that lncRNAs are emerging as key players in tissue physiology and 77 disease progression, including cancer, the mechanism identified in this study 78 may help decipher the mechanisms underlying KS pathogenesis induced by HIV 79 and KSHV co-infection. 80 followed Pathway and inhibition of these pathways was longer observed after HIV-Tat treatment. our study revealed a novel HIV-Tat interacting lncRNA LINC00313 that links the KSHV and HIV viral-viral interaction in mediating progression. summary, our work revealed LINC00313 as a lncRNA that is up-regulated during KSHV reactivation which inhibits endothelial cell migration and tube formation. Our biological studies together with bioinformatics analysis suggests that HIV-Tat can interact with LINC00313 and rescue the endothelial cell migration and tube formation ability inhibited by LINC00313. These results not only provide a potential mechanism by which HIV-Tat enhances endothelial cell angiogenesis function under KSHV reactivation conditions, but also suggest that the lncRNA-HIV-Tat axis may responsible interaction to Further will be needed to how up-regulated upon KSHV reactivation and whether KSHV regulated lncRNAs