Abstract
Increased life expectancy of patients diagnosed with HIV in the current era of antiretroviral therapy is unfortunately accompanied with the prevalence of HIV-associated neurocognitive disorders (HANDs) and risk of comorbidities such as Alzheimer-like pathology. HIV-1 transactivator of transcription (Tat) protein has been shown to induce the production of toxic neuronal amyloid protein and also enhance neurotoxicity. The contribution of astrocytes in Tat-mediated amyloidosis remains an enigma. We report here, in simian immunodeficiency virus (SIV)+ rhesus macaques and patients diagnosed with HIV, brain region–specific up-regulation of amyloid precursor protein (APP) and Aβ (40 and 42) in astrocytes. In addition, we find increased expression of β-site cleaving enzyme (BACE1), APP, and Aβ in human primary astrocytes (HPAs) exposed to Tat. Mechanisms involved up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the long noncoding RNA (lncRNA) BACE1‐antisense transcript (BACE1-AS), resulting, in turn, in the formation of the BACE1-AS/BACE1 RNA complex, subsequently leading to increased BACE1 protein, and activity and generation of Aβ-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1-AS/BACE1 in Tat-mediated amyloidosis. This is the first report implicating the role of the HIF-1α/lncRNABACE1-AS/BACE1 axis in Tat-mediated induction of astrocytic amyloidosis, which could be targeted as adjunctive therapies for HAND-associated Alzheimer-like comorbidity.
Highlights
The life span of individuals living with HIV-1 has significantly increased due to effective combination antiretroviral therapy
We first sought to assess the expression of toxic amyloid proteins and hypoxia-inducible factor (HIF-1α) in brain homogenates of chronically infected patients who are HIV positive and were diagnosed with either asymptomatic neurocognitive impairment or that had minor cognitive impairment
Patients infected with HIV with Alzheimer disease (AD)/cerebral ischemia were chosen as positive controls in addition to the uninfected group that served as negative controls
Summary
The life span of individuals living with HIV-1 has significantly increased due to effective combination antiretroviral therapy (cART). Despite suppressed viremia and increased life spans, there is continued high prevalence of HIV-associated neurocognitive disorder (HAND) [1,2] and other HIV-associated non-AIDS conditions that are closely associated with accelerated or premature aging of individuals infected with HIV [3]. Long-term usage of cART, all of which may predispose the individuals infected with HIV to age-related neurodegenerative disorders [4]. Chronic HIV infection and aging could intersect to impair global cognitive functioning [3]. A key co-pathogenic factor in the long-term survival of patients diagnosed with HIV treated with cART is age. One of the neuropathological findings in HIV-1 individuals is the deposition of amyloid β plaques in the brain, which in turn may contribute to the progression and pathology of HAND [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
