HIV-1 Tat Induced HIF-1α-LncRNA BACE 1-AS Mediated Astrocytic Amyloidogenesis: Implications For Alzheimer’s Like Neuropathology In HIV

Author(s): Shilpa Buch

Conference: Dubai One Health Conference

Publication Date: 23 June, 2023

Keywords: HIV, LncRNA, Amyloidogenesis, Alzheimer’s Disease, Astrocytes

Abstract

Increased Life Expectancy Of HIV+Ve Patients In The Post Highly Active Anti-Retroviral Therapy Era Parallels With Increased Incidence Of HIV-Associated Neurological Disorders (HAND) And Associated Comorbidities Such As Alzheimer’s Disease (AD). The Persistence Of HAND Is Thought To Involve Poor Penetration Of The Antiretroviral Drugs Across The BBB Into The CNS, Leading To Persistent Low-Level Viral Replication In The CNS With Accumulation Of Cytotoxic Viral Proteins Including Tat. Interestingly, There Have Been Reports On Tat-Mediated Production Of The Toxic Neuronal Amyloid Protein And The Interaction With The Former, Leading To Enhanced Toxicity. However, Abundant Glial Cells Such As The Astrocytes Have Also Garnered Interest As Potential Contributors Of Amyloidosis, And This Could Translate Into A Significant Added Burden To The Process Of Amyloidosis In The Context Of Tat. Therefore, The Present Study Was Hypothesized To Assess The Role Of Astrocytes In Mediating Tat Induced Amyloidosis Which, In Turn, Could Also Have A Significant Deleterious Effect On The Neurotoxicity Associated With HAND. Our In Vivo Data Showed That SIV+ Macaques/ HIV+Ve Patients, Have Brain Region Specific Upregulation Of The Amyloidogenic Components And The Regulatory Machinery In Both RNA And Protein Level, That Co-Localized With GFAP Positive Astrocytes, Thereby Underscoring The Contribution Of Astrocytes In The Development Of AD Like Symptoms Leading To The Process Of Neurodegeneration And Cognitive Impairments In HAND. In Vitro Findings Dissecting Out The Cell Type Specificity And Machinery Leading To Astrocytic Amyloidosis Revealed Upregulation Of AD Markers – BACE-1, Amyloid Precursor Protein (APP), AβmoC64, P-Tau, As Well As Increased Activity Of BACE-1 In Tat-Exposed Human Primary Astrocytes (HPA). Molecular Mechanism(S) Underlying This Process Involved Upregulation Of Hypoxia Inducible Factor (HIF-1α) With A Concomitant Translocation To The Nucleus And Binding To The LncRNA BACE-1AS Resulting In Formation Of A Unique Complex As Confirmed By RIP And EMSA. Further, ChIP Assay Showed Functional Binding Of The Complex To BACE-1 Promoter Leading In Turn, To Increased Expression Of BACE-1 By Transcriptional, Post Transcriptional And Translational Mechanisms Along With Increased Activity Leading To Consequential Generation Of Aβ-42 Protein Via Cleavage Of APP. Additionally, Gene Silencing Approaches Confirmed The Regulatory Role Of HIF-1α-BACE-1AS Axis In Aβ Generation. This Complex Of HIF-1α- LncRNA BACE1-AS Can Thus Be Targeted To Develop Adjunctive Therapy For HAND Patients On CART Therapy.