Fig 12. Schematic representation of HIV-1 Tat–induced astrocytic amyloidosis mediated by HIF-1α–lncRNA BACE1-AS axis.

HPAs exposed to HIV-1 Tat showed increased expression and accumulation of HIF-1α involving differential regulatory mechanisms—transcription, RNA stabilization (posttranscription), translation, and posttranslational stabilization (decreased expression of PHD-2) (1). Upon accumulation, HIF-1α is translocated into the nucleus, where it forms a complex with the lncRNA BACE1-AS (which is also up-regulated following HIV-1 Tat exposure).The HIF-1α–lncRNA BACE1-AS complex, in turn, binds to the BACE1 promoter to induce its transcription (2). Following transcriptional induction of BACE1 mRNA, it subsequently binds to the BACE1-AS, resulting, in turn, in stabilization of BACE1 mRNA (3). This then leads to increased translation and activity of BACE1 (4). Additionally, HIV-1 Tat has also been shown to induce the expression of APP mRNA, resulting in up-regulated expression of APP protein, which then is subject to cleavage by BACE1, leading to the release of various Aβ forms into the extracellular space. Oligomerization of the toxic Aβ forms leads to deposition of insoluble amyloid plaques in select brain regions, which are neurotoxic and can also independently interact with HIV-1 Tat to further aggravate HAND-associated toxicity. APP, amyloid precursor protein; Aβ, amyloid beta; BACE1, β-site cleaving enzyme; BACE1-AS, BACE1‐antisense transcript; HAND, HIV-associated neurocognitive disorder; HIF-1α, hypoxia-inducible factor; HPA, human primary astrocyte; lncRNA, long noncoding RNA; PHD-2, prolyl hydroxylase 2; Tat, transactivator of transcription. Original creation.