HIV-1 Tat Interacts with a Kaposi’s Sarcoma-Associated Herpesvirus Reactivation-Upregulated Antiangiogenic Long Noncoding RNA, LINC00313, and Antagonizes Its Function

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma (KS), an AIDS-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency virus (HIV)-infected AIDS patients has been ascribed to an interaction between HIV type 1 (HIV-1) and KSHV, focusing on secretory proteins. The HIV-1 secreted protein HIV Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long noncoding RNA (lncRNA) that interacts with HIV Tat. We found that LINC00313 overexpression inhibits cell migration, invasion, and tube formation, and this suppressive effect was relieved by HIV Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components, and this interaction was disrupted by HIV Tat, suggesting that LINC00313 may mediate transcription repression through recruitment of PRC2 and that HIV Tat alleviates repression through disruption of this association. This notion was further supported by bioinformatics analysis of transcriptome profiles in LINC00313 overexpression combined with HIV Tat treatment. Ingenuity Pathway Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell movement and migration pathways, and enrichment of these pathways was absent in the presence of HIV Tat. Collectively, our results illustrate that an angiogenic repressive lncRNA, LINC00313, which is upregulated during KSHV reactivation, interacts with HIV Tat to promote endothelial cell motility. These results demonstrate that an lncRNA serves as a novel connector in HIV-KSHV interactions. IMPORTANCE KS is a prevalent tumor associated with infections with two distinct viruses, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the virus-virus interaction associated with KS formation has focused on secretory factors. HIV Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA upregulated during KSHV lytic reactivation, as a novel HIV Tat-interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially by interacting with chromatin remodeling complex PRC2 and downregulation of cell migration-regulating genes. An interaction between HIV Tat and LINC00313 contributed to the dissociation of PRC2 from LINC00313 and the disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV coinfection.

Long non-coding RNAs and circular RNAs in tumor angiogenesis: From mechanisms to clinical significance

“…Mechanistically, LINC00313 blocks endothelial cell angiogenesis-related properties by binding to PRC2 and decreasing migration-regulating gene expression. 59 In addition to the interaction with PRC2, certain lncRNAs also bind to other epigenetic factors. Another hypoxia-mediated lncRNA, GATA6-AS, is upregulated in endothelial cells under hypoxic conditions.…”

Long Non-coding RNAs in Gammaherpesvirus Infections: Their Roles in Tumorigenic Mechanisms

“…MEG3 is downregulated in a variety of malignant tumors and acts as a tumor suppressor. LINC00313, which is upregulated by KSHV reactivation, was shown to interact with HIV Tat ( Yang et al, 2020 ).…”

New insights into pathogenesis point to HIV-1 Tat as a key vaccine target

“…This is due to the ability of Tat to mimic and/or enhance the effects of extracellular matrix molecules, which regulate and enhance the effects of angiogenic growth factors on endothelial cell growth and locomotion through RGD-binding integrins that function as Tat receptors [ 50 , 101 – 103 ]. Tat also induces angiogenesis and vascular permeability in synergy with angiogenic factors or inflammatory cytokines by activating matrix metalloproteinases (MMPs) [ 92 ] and promotes the recruitment of HHV-8-infected circulating KS cells into tissues [ 103 ], triggers HHV-8 reactivation from latency, and accelerates tumor progression induced by HHV-8-encoded oncoproteins [ 107 – 110 ] (Table 1 ).…”