Anti-nucleolin aptamer AS1411: Applications in Kaposi's Sarcoma Associated Herpes Virus (KSHV) biology

抗核仁素适体 AS1411：在卡波西肉瘤相关疱疹病毒 (KSHV) 生物学中的应用

• 批准号: 10619191
• 负责人: Neelam Sharma-Walia
• 金额: $ 21.88万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619191
• 关键词: Angiogenesis Inhibitors; Angiogenic Factor; Antibodies; Antiviral Agents; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; Biogenesis; Biology; Blood Vessels; Cell Death Induction; Cell Line; Cell Survival; Cells; Cellular Metabolic Process; Chemicals; Cyclophosphamide; DNA; Development; Diagnosis; Dose; Doxorubicin; Endothelial Cells; Endothelium; Environment; Etiology; Exhibits; Family; G-Quartets; Gene Expression; Gene Proteins; Genes; Growth Factor; HIV; HIV therapy; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 8; Human poliovirus; Immunocompromised Host; Incubated; Infection; Inflammatory; Integration Host Factors; Interleukin-6; Intervention; Kaposi Sarcoma; Knowledge; Lesion; Life Cycle Stages; Link; Lymphangiogenesis; Lymphoid Tissue; Lymphoma cell; Lytic; Lytic Phase; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic Pathway; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Oligonucleotides; Paracrine Communication; Pathogenesis; Pathway interactions; Patients; Pharmacy (field); Phase; Post-Transcriptional Regulation; Prednisone; Prognosis; Proliferating; Proteins; RNA-Binding Proteins; Respiratory syncytial virus; Ribosomes; Role; Safety; Serious Adverse Event; Shapes; Signal Transduction; Skin Kaposi' s Sarcoma; Skin Tissue; Syndrome; Telomerase; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Translational Regulation; Vascular Endothelial Cell; Vincristine; Viral; Viral Cancer; Viral Genes; Viral Regulatory Proteins; Virion; angiogenesis; anti-cancer; antiretroviral therapy; aptamer; autocrine; body cavity; cancer therapy; chemotherapy; chromatin remodeling; co-infection; cytokine; effusion; gammaherpesvirus; hematopoietic tissue; histone modification; in vitro Model; in vivo Model; latency-associated nuclear antigen; latency-associated protein; member; mortality; novel; nucleolin; primary effusion lymphoma; programs; rare cancer; skin lesion; theranostics; tumor; tumorigenic; uptake

Kaposi’s sarcoma-associated herpesvirus (KSHV), a member of the human γ-herpesvirus family is also termed as human herpesvirus type 8 (HHV-8). KSHV is an etiological agent of an endothelial tumor called Kaposi’s sarcoma (KS) and a highly aggressive lymphoproliferative B cell lymphoma called primary effusion lymphoma (PEL). KS is the most common vascular malignancy causing high morbidity and mortality in HIV-infected patients. PEL is a rare tumor of hematopoietic and lymphoid tissues and is associated with a poor prognosis. PEL cases have been dramatically reduced in the US since the widespread use of combined antiretroviral therapy (cART) but KSHV still causes significant mortality in the developing world. There is a critical need in KSHV targeting specific antiviral drugs, which are very well tolerated with no severe adverse events for immunocompromised patients with KSHV associated malignancies. KSHV exhibits two distinct phases in its life cycle. During latency, a minimal number of latency genes such as vFLIP (ORF71), vCyclin (ORF72), latency-associated nuclear antigen-1 (LANA-1; ORF73), and Kaposin are expressed. By contrast, during the lytic phase, KSHV expresses a wide array of immediate-early (IE), delayed-early (DE), and late genes; undergo active replication and produce virion progeny. KSHV has been shown to utilize multiple host growth factors, cytokines, angiogenic factors, and cell signaling and metabolism-related proteins for creating a beneficial environment for its replication, survival, and latency. Our exciting studies discovered that: 1) KS skin lesions express remarkably robust expression of nucleolin compared to healthy skin tissue; 2) KSHV de novo infection in primary endothelial cells induced a high level of nucleolin and phospho-nucleolin, and more importantly, 3) Incubation of KSHV infected cells with G- quadruplex forming anti-nucleolin aptamer AS1411 reduced KSHV latent (ORF73) and increased lytic (ORF50) gene expression and we obtained similar results in nucleolin silenced KSHV infected PEL cells. 4) AS1411 treatment was efficacious in inducing cell death in KSHV infected PEL cell lines. Based on our preliminary results, we hypothesize that KSHV induces host factor nucleolin to support its latency and life cycle and targeting nucleolin with AS1411 would have therapeutic potential in KSHV associated malignancies. To test this hypothesis, we have formulated two specific aims in which we will 1) To determine the regulatory mechanisms of nucleolin expression upon KSHV infection and its role in KSHV latency, and 2) To evaluate the chemotherapeutic potential of using AS1411 to treat KS and PEL. Our studies are significant and will have a positive impact by advancing the unexplored and novel targeted theranostic field of aptamers in KSHV biology and understanding their antiviral and anticancer potential can also be applied to other viral malignancies.

卡波西肉瘤相关疱疹病毒（KSHV）是人类γ-疱疹病毒家族的一员