title: Activation status of integrated stress response pathways in neurones and astrocytes of HIV-associated neurocognitive disorders (HAND) cortex.
abstract: OBJECTIVE
  Combined anti-retroviral therapy (cART) has led to a reduction in the incidence of HIV-associated dementia (HAD), a severe motor/cognitive disorder afflicting HIV(+) patients. However, the prevalence of subtler forms of neurocognitive dysfunction, which together with HAD are termed HIV-associated neurocognitive disorders (HAND), continues to escalate in the post-cART era. The microgliosis, astrogliosis, dendritic damage, and synaptic and neuronal loss observed in autopsy cases suggest an underlying neuroinflammatory process, due to the neurotoxic factors released by HIV-infected/activated macrophages/microglia in the brain, might underlie the pathogenesis of HAND in the post-cART era. These factors are known to induce the integrated stress response (ISR) in several neurodegenerative diseases; we have previously shown that BiP, an indicator of general ISR activation, is upregulated in cortical autopsy tissue from HIV-infected patients. The ISR is composed of three pathways, each with its own initiator protein: PERK, IRE1α and ATF6.
  
  
  METHODS
  To further elucidate the specific ISR pathways activated in the central nervous system of HAND patients, we examined the protein levels of several ISR proteins, including ATF6, peIF2α and ATF4, in cortical tissue from HIV-infected patients.
  
  
  RESULTS
  The ISR does not respond in an all-or-none fashion in HAND, but rather demonstrates a nuanced activation pattern. Specifically, our studies implicate the ATF6 pathway of the ISR as a more likely candidate than the PERK pathway for increases in BiP levels in astrocytes.
  
  
  CONCLUSIONS
  These findings begin to characterize the nature of the ISR response in HAND and provide potential targets for therapeutic intervention in this disease.
authors: Department of Pathology, School of Dental Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6030, USA.
authors: C
authors: C
authors: Akay
authors: K A
authors: KA
authors: Lindl
authors: N
authors: N
authors: Shyam
authors: B
authors: B
authors: Nabet
authors: Y
authors: Y
authors: Goenaga-Vazquez
authors: J
authors: J
authors: Ruzbarsky
authors: Y
authors: Y
authors: Wang
authors: D L
authors: DL
authors: Kolson
authors: K L
authors: KL
authors: Jordan-Sciutto
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D051702:Activating Transcription Factor 6; D000328:Adult; D001253:Astrocytes / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D004722:Endoribonucleases / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; C487807:ATF6B protein, human; D051702:Activating Transcription Factor 6; D050976:Basic-Leucine Zipper Transcription Factors; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D018840:HSP70 Heat-Shock Proteins; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases