A Rat Model of EcoHIV Brain Infection

Abstract

It has been well studied that the EcoHIV infected mouse model is of significant utility in investigating HIV associated neurological complications. Establishment of the EcoHIV infected rat model for studies of drug abuse and neurocognitive disorders, would be beneficial in the study of neuroHIV and HIV-1 associated neurocognitive disorders (HAND). In the present study, we demonstrate the successful creation of a rat model of active HIV infection using chimeric HIV (EcoHIV). First, the lentiviral construct of EcoHIV was packaged in cultured 293 FT cells for 48 hours. Then, the conditional medium was concentrated and titered. Next, we performed bilateral stereotaxic injections of the EcoHIV-EGFP into F344/N rat brain tissue. One week after infection, EGFP fluorescence signals were detected in the infected brain tissue, indicating that EcoHIV successfully induces an active HIV infection in rats. In addition, immunostaining for the microglial cell marker, Iba1, was performed. The results indicated that microglia were the predominant cell type harboring EcoHIV. Furthermore, EcoHIV rats exhibited alterations in temporal processing, a potential underlying neurobehavioral mechanism of HAND as well as synaptic dysfunction eight weeks after infection. Collectively, the present study extends the EcoHIV model of HIV-1 infection to the rat offering a valuable biological system to study HIV-1 viral reservoirs in the brain as well as HAND and associated comorbidities such as drug abuse.

Figure 1.. The EcoHIV-EGFP infected cells distributed in rat brain.

(A) The representative confocal images (20x) of EcoHIV-EGFP expression in hippocampal dentate gyrus or cortex regions at 7 days after injection. (B) The representative confocal images (60X) of co-localization of Iba1 immunostaining with EcoHIV-EGFP infected cells at 7 days after injection.

Figure 2.. EcoHIV infection induced prominent neurocognitive deficits in temporal processing.

Visual gap prepulse inhibition was conducted eight weeks after stereotaxic injections of either EcoHIV or saline. EcoHIV infection induced prominent alterations in temporal processing evidenced by the relative insensitivity to the manipulation of interstimulus interval relative to control rats. Detailed methodology described in McLaurin et al..

Figure 3.. Infectivity with EcoHIV-EGFP altered the morphological parameters of dendritic spines, supporting profound synaptic dysfunction.

EcoHIV rats displayed profound alterations in dendritic spine morphology, evidenced by an increased relative frequency of shorter dendritic spines (A) with an increased head diameter (B) and increased neck diameter (C) relative to control animals.