Evolution of the HIV-1 transgenic rat: utility in assessing the progression of HIV-1-associated neurocognitive disorders

Abstract

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.

Male HIV‐1 transgenic rats show reduced cocaine‐maintained lever‐pressing compared to F344 wildtype rats despite similar baseline locomotion

“…Rats were fed immediately following daily sessions a sufficient amount of chow to maintain them at no less than 95% of presurgical free‐feeding body weights. In line with previous reports, Tg rats weighed less than WT rats (McLaurin et al, ; Moran, Booze, Webb, & Mactutus, 2013; Peng et al, 2010). This difference highlights the import of infusing a drug based on a rat's body weight (see Drug section).…”

“…At the start of the experiment, before cocaine self‐administration developed in any of the rats, there was no discernable difference between Tg and WT rats in baseline chamber activity. Although past work has reported some locomotor impairment in HIV‐1 Tg rats over the WT rats (e.g., June et al, 2009; McLaurin et al, ), this finding is not universal (e.g., Kaas et al, 2010; Liu et al, 2009). Though a systematic experiment has not been conducted, our read of the literature suggests that size and familiarity of the environment may be important factors.…”

“…One possible account we considered was that expression of the genetic mutation in HIV-1 Tg rats translated functionally into a learning impairment in our task. Indeed, relative to WT rats, Tg rats show behavioral deficits in such tasks as pre-pulse inhibition (McLaurin et al, 2018;Moran, Booze, & Mactutus, 2013), Morris Water Maze (Vigorito et al, 2007), and fear conditioning (Nesil et al, 2015). However, our enthusiasm for this possibility is diminished by the demonstration of cocaine self-administration by McIntosh et al (2015) and Wayman et al (2016) without any reported preliminary training phase in which responding (lever-press or nose-poke) was first trained with food reinforcement.…”

“…Cocaine was generously supplied by the NIDA Drug Supply Program. These data in their raw form were made freely available on the Open Science Framework osf.io/xtygc/ The development of the HIV-1 transgenic (Tg) rat, which expresses a noninfectious HIV-1 provirus (pEVd1143) and therefore produces similar neurological impairments, has been a valuable experimental tool for examining neural immune deficiencies (Chang et al, 2014;McLaurin, Booze, & Mactutus, 2018;Reid et al, 2016;Reid et al, 2001). For these rats, the provirus contained the HIV-1 genome with a functional gag-pol-deletion, a truncation that prevents viral replication while maintaining viral protein expression (Vigorito, Connaghan, & Chang, 2015).…”

Optimizing animal models for HIV-associated CNS dysfunction and CNS reservoir research

“…HIV-1 transgenic rats contain a gag-poldeleted HIV-1 provirus located on chromosome 9 in F344/N strain. McLaurin et al (McLaurin et al 2017) describe utility of the transgenic rats in longitudinal experimental designs to determine the progression of HAND. They begin by validating the integrity of auditory and visual sensory system function in transgenic rats, using cross-modal prepulse inhibition and locomotor activity assessments.…”