Selective developmental alterations in The HIV-1 transgenic rat: Opportunities for diagnosis of pediatric HIV-1

Abstract

Since the advent of combination antiretroviral therapy (cART), pediatric HIV-1 (PHIV) has evolved from a fatal disease to a chronic disease as children perinatally infected with HIV-1 survive into adulthood. The HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes constitutively throughout development, was used to model the early development of chronic neurological impairment in PHIV. Male and female Fischer HIV-1 Tg and F344N control rats, sampled from 35 litters, were repeatedly assessed during early development using multiple experimental paradigms, including somatic growth, locomotor activity, cross-modal prepulse inhibition (PPI) and gap-prepulse inhibition (gap-PPI). Later eye opening was observed in HIV-1 Tg animals relative to controls. HIV-1 Tg animals exhibited a shift in the development of locomotor activity implicating alterations in the maturation of the forebrain cholinergic inhibitory system. Alterations in the development of PPI and perceptual sharpening were observed in both auditory and visual PPI as indexed by a relative insensitivity to the dimension of time (ms for ISI; days of age for perceptual sharpening) as a function of the HIV-1 transgene. Presence of the HIV-1 transgene was diagnosed with 97.1% accuracy using auditory and visual PPI measurements from PD 17 and 21. Early selective developmental alterations observed in the HIV-1 Tg rats provide an opportunity for the development of a point-of-care screening tool, which would permit for early diagnosis of PHIV and improve the long-term outcome for children perinatally infected with HIV-1.

Temporal processsing demands in the HIV‐1 transgenic rat: Amodal gating and implications for diagnostics

“…The monotonic relationship present in gap threshold detection provides a distinct advantage for the development of a clinical diagnostic screening tool. However, it must be noted that the presence of the HIV‐1 transgene can be diagnosed with high accuracy (i.e., ≥90%) using assessments of temporal processing (i.e., cross‐modal PPI, gap‐PPI, and gap threshold detection) regardless of the monotonicity of the function (McLaurin et al, 2016a,b,c). Thus, the present study continues to provide strong evidence for the utility of temporal processing deficits as a clinically relevant diagnostic screening tool for HAND.…”

Dose‐dependent neurocognitive deficits following postnatal day 10 HIV‐1 viral protein exposure: Relationship to hippocampal anatomy parameters

“…A comparative summary of findings in the present P10 study and the previous P1 study is illustrated in Table 4. In preweanling HIV‐1 Tg rats, which express viral proteins constitutively throughout development, neurocognitive assessments revealed significant alterations in both prepulse inhibition and locomotor activity (McLaurin et al, 2017a); neurocognitive deficits which were similar to those reported following early viral protein exposure (P1; Fitting et al, 2008b; Moran et al, 2014a). Thus, collectively, these studies provide strong evidence for the effect of timing on the development of neurocognitive impairment, with early viral protein exposure (P1, HIV‐1 Tg rat) having a more deleterious effects on the developing CNS than late viral protein exposure (P10).…”

“…Findings revealed a significant increase in phosphorylated tyrosine hydroxylase protein expression and a decrease in dopamine transporter (DAT) mRNA, without changes in tyrosine hydroxylase or DAT protein in the HIV-1 transgenic rat midbrain, suggesting selective vulnerability of the DA system in developing brains to HIV-1 infection (Webb et al, 2010). Additionally, HIV-1 Tg rats assessed throughout the lifespan in neurocognitive tasks tapping the DA system, exhibited significant alterations in temporal processing (Moran et al, 2013a;McLaurin et al, 2016McLaurin et al, , 2017a, habituation (Chang and Vigorito, 2006;Moran et al, 2013b;Reid et al, 2016b;McLaurin et al, 2017d), sustained attention (Moran et al, 2014b), working memory (Repunte-Canonigo et al, 2014) and spatial learning (Vigorito et al, 2007;Lashomb et al, 2009).…”

“…Although preclinical and clinical studies have characterized HIV-1 associated neurocognitive disorders (HAND) in adults (e.g., review, Woods et al, 2009;Heaton et al, 2010), neurocognitive deficits in HIVinfected children are poorly understood (Crowell et al, 2014). A limited number of preclinical studies have focused on the effects of early exposure to HIV-1 viral toxic proteins on the development of neurocognitive disorders, independent of the virus itself (Bussiere et al, 1999;Fitting et al, 2008b;Webb et al, 2009;Moran et al, 2014a;Fitting et al, 2015;McLaurin et al, 2017a). Specifically, stereotaxic injections of the viral proteins Tat and/or gp120 on P1 revealed deleterious effects on multiple reflexive, preattentive (e.g., prepulse inhibition (PPI)), and neurocognitive assessments (e.g., Morris water maze), as well as alterations in anatomical parameters of the hippocampus (Fitting et al, 2008a,b;Moran et al, 2014a).…”

Modulatory Effects of Nicotine on neuroHIV/neuroAIDS

“…This model has been demonstrated to mimic HIV-1–infected patients receiving cART, who have suppressed viral replication (Peng et al 2010). A number of reports have shown abnormal changes in the HIV-1Tg rats, for instance, lower body weight (Peng et al 2010), immune-response alterations (Reid et al 2001), T-cell abnormalities (Reid et al 2004), kidney failure (Ray et al 2003), neurobehavioral and spatial learning and memory changes (Vigorito et al 2007; Lashomb et al 2009; Moran et al 2013), neuronal dysfunction (Reid et al 2016), immunophenotype and cellular response alterations (Abbondanzo and Chang 2014), neurocognitive deficits in pediatric HIV-1 (McLaurin et al 2016, 2017), and gene expression alterations in various brain regions (Li et al 2013). Therefore, this rat is a more suitable animal model, without expensive high-level biosafety demands, for studying the mechanisms of HIV-associated disease in the post-cART era.…”