Human Endogenous Retrovirus-K(II) Envelope Induction Protects Neurons during HIV/AIDS

Abstract

Human endogenous retroviruses (HERVs) are differentially expressed depending on the cell type and physiological circumstances. HERV-K has been implicated in the pathogenesis of several diseases although the functional consequences of its expression remain unknown. Human immunodeficiency virus (HIV) infection causes neuroinflammation with neuronal damage and death. Herein, we investigated HERV-K(II)/(HML-2) envelope (Env) expression and its actions in the brain during HIV/AIDS. HERV-K(II) Env expression was assessed in healthy brain tissues, autopsied HIV HIV− infected (HIV+) and uninfected (HIV−) brains and in neural cell cultures by real time RT-PCR, massively parallel (deep) sequencing, immunoblotting and immunohistochemistry. Neuronal and neural stem cells expressing HERV-K(II) Env were analyzed in assays of host responses including cellular viability, immune responses and neurobehavioral outcomes. Deep sequencing of human brain transcriptomes disclosed that RNA sequences encoded by HERV-K were among the most abundant HERV sequences detected in human brain. Comparison of different cell types revealed that HERV-K(II) env RNA abundance was highest in cultured human neurons but was suppressed by epidermal growth factor exposure. HERV-K(II) Env immunoreactivity was increased in the cerebral cortex from persons with HIV/AIDS, principally localized in neurons. Human neuronal cells transfected with HERV-K(II) Env exhibited increased NGF and BDNF expression. Expression of HERV-K(II) Env in neuronal cells increased cellular viability and prevented neurotoxicity mediated by HIV-1 Vpr. Intracerebral delivery of HERV-K(II) Env expressed by neural stem cells suppressed TNF-α expression and microglial activation while also improving neurobehavioral deficits in vpr/RAG1−/− mice. HERV-K(II) Env was highly expressed in human neurons, especially during HIV/AIDS, but in addition exerted neuroprotective effects. These findings imply that HERV gene products might exert adaptive effects in circumstances of pathophysiological stress, perhaps underlying the conservation of HERVs within the human genome.

TDP-43 regulates endogenous retrovirus-K viral protein accumulation

“…Inflammatory signalling pathways are crucial for driving ERVK expression (Manghera and Douville, 2013;Manghera et al, 2015). Infectious agents, such as HIV, can also trigger ERVK expression (Bhardwaj et al, 2014;Bhat et al, 2014;Vincendeau et al, 2015). Transmissible human retroviruses have been associated with an increased incidence of ALS-like syndromes (Matsuzaki et al, 2000;Verma and Berger, 2006), with anti-retroviral therapy reversing neurological symptoms (MacGowan et al, 2001;Moulignier et al, 2001).…”

“…Transmissible human retroviruses have been associated with an increased incidence of ALS-like syndromes (Matsuzaki et al, 2000;Verma and Berger, 2006), with anti-retroviral therapy reversing neurological symptoms (MacGowan et al, 2001;Moulignier et al, 2001). A biological link between HIV neuroinvasion and ALS is the re-activation of neuron-expressed ERVK (Bhat et al, 2014;Douville et al, 2011). In HIV, cortical neurons exhibit enhanced ERVK envelope protein expression, which is postulated to be neuroprotective (Bhat et al, 2014).…”

“…A biological link between HIV neuroinvasion and ALS is the re-activation of neuron-expressed ERVK (Bhat et al, 2014;Douville et al, 2011). In HIV, cortical neurons exhibit enhanced ERVK envelope protein expression, which is postulated to be neuroprotective (Bhat et al, 2014).…”

ALSUntangled 45: Antiretrovirals

“…These mice had decreased counts of upper and lower motor neurons and developed a disease characterized by progressive muscle weakness with clinical features and muscle biopsy findings similar to human ALS (11). However, these findings are not entirely consistent with prior studies that found HERV Env expression in a human neuroblastoma cell line increased expression of neuronal growth factors and was protective against some neurotoxins in a mouse neuroblastoma cell line (34). These discrepancies could be due to the use of different cell lines, use of slightly different HERV type K Env proteins, or use of different experimental methods to judge cellular injury.…”

Application of “Omics” Technologies for Diagnosis and Pathogenesis of Neurological Infections

“…HIV infection of the brain is characterized by microglial and astrocyte activation and the induction of numerous proinflammatory cytokines and mediators. Nonetheless, sequence tags derived from the brains of HIVinfected individuals showed a preponderance of human endogenized retroviral RNA sequence elements belonging to the human endogenous retrovirus-K (HERV-K (II)) family compared to uninfected individuals that were chiefly located in neurons and subsequently shown to exert neuroprotective effects [14].…”