Role of APP-related circRNAs induced by HIV-1 infection in beta-amyloid formation

Abstract: Almost 50% of people living with HIV-1 (PLWH) under combination antiretroviral therapy (cART) still show milder forms of HIV-1 associated neurocognitive disorders (HAND). HAND shows the main molecular hallmarks of Alzheimer's disease (AD), including dysregulation of function and expression of amyloid precursor protein (APP), β-secretase and presenilin-1 (PSEN-1). HIV-1 promotes chronic neuroinflammatory microenvironments through latent activation in aging PLWH, and Aβ formation has also been observed in an age-dependent manner. However, the cause of HAND progression in PLWH and the role of HIV in Aβ formation are not truly understood. Recent studies have considered the accumulation of Aβ as result of a viral escape strategy adopted by HIV-1 in microglial cells in the brain. It has been also described that alternative splicing of APP results in generation of circular RNAs (circRNA), essential members of so-called competing endogenous RNA networks (or ceRNA, circRNA/microRNA/mRNA) involved in regulating gene expression. CircRNAs are generated by back-splicing and can bind multiple microRNAs and inhibit their function, acting as microRNA sponges, or can be translated into protein. Two circRNAs, the circ_0007556 which is derived from the APP gene, and the circ_0004381, have been recently described in association with AD. Interestingly, it has been recently demonstrated that circ_0007556 could be an alternative template for Aβ peptide translation. Moreover, inhibition of circ_0004381 improved the cognitive function via miR-647/PSEN1 axis in a murine AD model. Our preliminary data from HIV-1 infected human cerebral organoids (hCOs) suggest that expression of circ_0007556 is upregulated in HIV-1 infected organoids independently from cART treatment. In addition, we found that the circ_0004381 is downregulated by HIV-1 in hCOs and its expression is rescued by cART. Based on our preliminary data, we hypothesized that circ_0007556 and circ_0004381 may be involved in the Aβ accumulation induced by HIV-1, and HIV-1 infection may dysregulate the events involved in generation of Aβ to sustain the productive release of infectious viral particles. Therefore, we propose that the modulation of these circRNAs may provide mechanistic and functional data on the involvement of Aβ accumulation in HIV-1 infected brain and be an elective new target for the development of novel therapeutic interventions.