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.

Grant Number: 1R21AG092247-01A1
NIH Institute/Center: NIH
Principal Investigator: Anna Bellizzi