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.

Understanding the progression of HIV-1-associated neurocognitive disorders (HAND) is a critical need as the prevalence of HIV-1 in older individuals (>50 years) is markedly increasing due to the great success of combination antiretroviral therapy (cART). Longitudinal experimental designs, in comparison to cross-sectional studies, provide an opportunity to establish age-related disease progression in HAND. The HIV-1 transgenic (Tg) rat, which has been promoted for investigating the effect of long-term HIV-1 viral protein exposure, was used to examine two interrelated goals. First, to establish the integrity of sensory and motor systems through the majority of the animal's functional lifespan. Strong evidence for intact sensory and motor system function through advancing age in HIV-1 Tg and control animals was observed in cross-modal prepulse inhibition (PPI) and locomotor activity. The integrity of sensory and motor system function suggested the utility of the HIV-1 Tg rat in investigating the progression of HAND. Second, to assess the progression of neurocognitive impairment, including temporal processing and long-term episodic memory, in the HIV-1 Tg rat; the factor of biological sex was integral to the experimental design. Cross-modal PPI revealed significant alterations in the development of temporal processing in HIV-1 Tg animals relative to controls; alterations which were more pronounced in female HIV-1 Tg rats relative to male HIV-1 Tg rats. Locomotor activity revealed deficits in intrasession habituation, suggestive of a disruption in long-term episodic memory, in HIV-1 Tg animals. Understanding the progression of HAND heralds an opportunity for the development of an advantageous model of progressive neurocognitive deficits in HIV-1 and establishes fundamental groundwork for the development of neurorestorative treatments.

The persistence of HIV-1 viral reservoirs in the brain, despite treatment with combination antiretroviral therapy (cART), remains a critical roadblock for the development of a novel cure strategy for HIV-1. To enhance our understanding of viral reservoirs, two complementary studies were conducted to (1) evaluate the HIV-1 mRNA distribution pattern and major cell type expressing HIV-1 mRNA in the HIV-1 transgenic (Tg) rat, and (2) validate our findings by developing and critically testing a novel biological system to model active HIV-1 infection in the rat. First, a restricted, region-specific HIV-1 mRNA distribution pattern was observed in the HIV-1 Tg rat. Microglia were the predominant cell type expressing HIV-1 mRNA in the HIV-1 Tg rat. Second, we developed and critically tested a novel biological system to model key aspects of HIV-1 by infusing F344/N control rats with chimeric HIV (EcoHIV). In vitro, primary cultured microglia were treated with EcoHIV revealing prominent expression within 24 h of infection. In vivo, EcoHIV expression was observed seven days after stereotaxic injections. Following EcoHIV infection, microglia were the major cell type expressing HIV-1 mRNA, results that are consistent with observations in the HIV-1 Tg rat. Within eight weeks of infection, EcoHIV rats exhibited neurocognitive impairments and synaptic dysfunction, which may result from activation of the NogoA-NgR3/PirB-RhoA signaling pathway and/or neuroinflammation. Collectively, these studies enhance our understanding of HIV-1 viral reservoirs in the brain and offer a novel biological system to model HIV-associated neurocognitive disorders and associated comorbidities (i.e., drug abuse) in rats.

The HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes, was used to investigate the effect(s) of long-term HIV-1 viral protein exposure on chronic neurocognitive deficits observed in pediatric HIV-1 (PHIV). A longitudinal experimental design was used to assess the progression of temporal processing deficits, a potential underlying dimension of neurocognitive impairment in HIV-1. Gap prepulse inhibition (gap-PPI), a translational experimental paradigm, was conducted every thirty days from postnatal day (PD) 30 to PD 180. HIV-1 Tg animals, regardless of sex, displayed profound alterations in the development of temporal processing, assessed using prepulse inhibition. A differential sensitivity to the manipulation of interstimulus interval was observed in HIV-1 Tg animals in comparison to control animals. Moreover, presence of the HIV-1 transgene was diagnosed with 90.8% accuracy using measures of prepulse inhibition and temporal sensitivity. Progression of temporal processing deficits in the HIV-1 Tg rat affords a relatively untapped opportunity to increase our mechanistic understanding of the role of long-term exposure to HIV-1 viral proteins, observed in pediatric HIV-1, in the development of chronic neurological impairment, as well as suggesting an innovative clinical diagnostic screening tool.

Despite the success of combination antiretroviral therapy (cART), approximately 50% of HIV-1 seropositive individuals develop HIV-1 associated neurocognitive disorders (HAND). Unfortunately, point-of-care screening tools for HAND lack sensitivity and specificity, especially in low-resource countries. Temporal processing deficits have emerged as a critical underlying dimension of neurocognitive impairments observed in HIV-1 and may provide a key target for the development of a novel point-of-care screening tool for HAND. Cross-modal prepulse inhibition (PPI; i.e., auditory, visual, or tactile prepulse stimuli) and gap-prepulse inhibition (gap-PPI; i.e., auditory, visual or tactile prepulse stimuli), two translational experimental paradigms, were used to assess the nature of temporal processing deficits in the HIV-1 transgenic (Tg) rat. Cross-modal PPI revealed a relative insensitivity to the manipulation of interstimulus interval (ISI) in HIV-1 Tg rats in comparison to controls, regardless of prestimulus modality. Gap-PPI revealed an insensitivity to the manipulation of ISI, independent of modality, in HIV-1 Tg rats in comparison to control animals. Manipulation of context (i.e., concurrent visual or tactile stimulus) in auditory PPI revealed a differential sensitivity in HIV-1 Tg animals compared to controls. The potential utility of amodal temporal processing deficits as an innovative point-of-care screening tool was explored using a discriminant function analysis, which diagnosed the presence of the HIV-1 transgene with 97.4% accuracy. Thus, the presence of amodal temporal processing deficits in the HIV-1 Tg rat supports the hypothesis of a central temporal processing deficit in HIV-1 seropositive individuals, heralding an opportunity for the development of a point-of-care screening tool for HAND.