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 extantin vivoanimal 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.

Since the introduction of combination antiretroviral therapy (cART) in the mid-90s, the most severe forms of HIV-1-associated neurocognitive disorders (HAND) have diminished. However, milder forms of HAND remain prevalent. Basic and clinical studies implicate alterations in the dopaminergic (DAergic) system in HIV-1 infection. We used the Fischer 344 HIV-1 transgenic (HIV-1 Tg) rat, which expresses 7 of the 9 HIV-1 genes, to examine potential DAergic alterations. Animals were studied beginning at 35 days of age to assess early-onset DAergic alterations, well before any documented neurological symptoms or clinical signs of “wasting”. At 48 hr intervals, animals were administered a single dose of methamphetamine (METH) (0, 0.5, 1, 2.5 and 5 mg/kg/ml s.c.) and tested for the auditory startle response (ASR) and prepulse inhibition (PPI), using an auditory prepulse [85dB(A) broad-band noise stimulus] and an auditory startle stimulus [100 dB(A) broad-band noise stimulus] in a sound-attenuating chamber with a continuous 70dB(A) white noise background. The protocol used a 5-min acclimation period, 6 startle trials, and 36 PPI trials [ISIs of 0, 8, 40, 80, 120, and 4000 ms, 6-trial blocks, Latin square design]. As the dose of METH increased, PPI of the startle response decreased. The HIV-1 Tg rats displayed a greater dose-dependency to the METH-induced disruption of PPI compared to non-transgenic controls. Western blot analysis of midbrain extracts revealed lower tyrosine hydroxylase (TH) protein levels and higher monoamine oxidase A (MAO-A) protein levels in HIV-1 Tg rats treated with METH compared to non-transgenic controls. Early-detected cognitive alterations in the preattentive process of sensorimotor gating may have significant predictive utility regarding the progression of DAergic alterations in HIV-1 infection.