Disruption of Timing: NeuroHIV Progression in the Post-cART Era

Sci Rep. 2019 Jan 29;9(1):827. doi: 10.1038/s41598-018-36822-1.

Abstract

The marked increase in life expectancy for HIV-1 seropositive individuals, following the great success of combination antiretroviral therapy (cART), heralds an examination of the progression of HIV-1 associated neurocognitive disorders (HAND). However, since the seminal call for animal models of HIV-1/AIDS in 1988, there has been no extant in vivo animal model system available to provide a truly longitudinal study of HAND. Here, we demonstrate that the HIV-1 transgenic (Tg) rat, resembling HIV-1 seropositive individuals on lifelong cART, exhibits age-related, progressive neurocognitive impairments (NCI), including alterations in learning, sustained attention, flexibility, and inhibition; deficits commonly observed in HIV-1 seropositive individuals. Pyramidal neurons from layers II-III of the medial prefrontal cortex (mPFC) displayed profound synaptic dysfunction in HIV-1 Tg animals relative to controls; dysfunction that was characterized by alterations in dendritic branching complexity, synaptic connectivity, and dendritic spine morphology. NCI and synaptic dysfunction in pyramidal neurons from layers II-III of the mPFC independently identified the presence of the HIV-1 transgene with at least 78.5% accuracy. Thus, even in the absence of sensory or motor system deficits and comorbidities, HAND is a neurodegenerative disease characterized by age-related disease progression; impairments which may be due, at least partly, to synaptic dysfunction in the mPFC. Further, the progression of HAND with age in the HIV-1 Tg rat and associated synaptic dysfunction affords an instrumental model system for the development of therapeutics and functional cure strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Dementia Complex / pathology*
  • AIDS Dementia Complex / virology
  • Animals
  • Disease Models, Animal
  • Female
  • HIV-1
  • Male
  • Neurodegenerative Diseases / pathology*
  • Neurodegenerative Diseases / virology
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / pathology
  • Prefrontal Cortex / virology
  • Pyramidal Cells / pathology*
  • Pyramidal Cells / virology
  • Rats
  • Rats, Transgenic