Characterization of a novel host cellular factor involved in HIV-1 neuropathogenesis

HIV-1 causes progressive neurological disorders collectively known as HIV-associated neurocognitive disorders (HAND). HAND is considered and umbrella term that encompasses three major stages: Asymptomatic neurocognitive impairment (ANI), mild/moderate neurocognitive disorder (MND), and HIV-associated dementia (HAD). The prevalence of HAND has increased despite the use of combined antiretroviral therapy (cART) and still affects 20 – 40% of HIV-1 infected individuals. The underlying cause of HAND observed in a particular set of subjects has not yet been fully elucidated nor have there been any ways to determine if an infected individual will eventually progress to HAND.\ud Previously we have shown that neurogranin (NRGN), a protein involved in the protein kinase C pathway and binds calmodulin (CaM) to decrease the threshold for long-term potentiation (LTP), which is involved in learning and memory is significantly downregulated in patients with high viral load at the mRNA level. With this in mind we theorize that there is a possible microRNA (miRNA) interaction with the 3’UTR of NRGN. We hypothesize that dysregulation of NRGN may be in part associated with development of HAND. To further understand the role of NRGN, we propose to delineate the role of NRGN and the mechanism(s) involved in HIV-1 induced degradation of NRGN. \ud The public health significance is in determining contributors to the degradation of cognition in HIV-1 infected individuals that progress to HAND, treatments can be developed to combat the effects on HIV-1 on proteins and cells pertinent to normal brain function.\u