The HIV-1 transgenic rat model of neuroHIV

Abstract

Despite the ability of current combination anti-retroviral therapy (cART) to limit the progression of HIV-1 to AIDS, HIV-positive individuals continue to experience neuroHIV in the form of HIV-associated neurological disorders (HAND), which can range from subtle to substantial neurocognitive impairment. NeuroHIV may also influence substance use, abuse, and dependence in HIV-positive individuals. Because of the nature of the virus, variables such as mental health co-morbidities make it difficult to study the interaction between HIV and substance abuse in human populations. Several rodent models have been developed in an attempt to study the transmission and pathogenesis of the HIV-1 virus. The HIV-1 transgenic (HIV-1Tg) rat is a reliable model of neuroHIV because it mimics the condition of HIV-infected patients on cART. Research using this model supports the hypothesis that the presence of HIV-1 viral proteins in the central nervous system increases the sensitivity and susceptibility of HIV-positive individuals to substance abuse.

Characterization of neuropathology in the HIV-1 transgenic rat at different ages

“…In view of what seems like a less prominent role for microglial activation in this model, we concur with previous studies asserting prolonged exposure to viral proteins as the main cause of neuropathology in the Tg rat (Midde, Gomez, 2011, Peng, Vigorito, 2010, Royal, Zhang, 2012, Vigorito, Connaghan, 2015, Wayman, Chen, 2015). Interestingly, we were able to detect serum gp120 in older but not in younger rats.…”

“…This however can be explained by the inherent differences between the two animal models as far as pathophysiology: the HIV humanized mouse is an immunodeficient model (NOD/scid-IL-2Rgamma(c)(null) mice) reconstituted with human hematopoietic CD34(+) stem cells and infected with HIV, thus reflecting human HIV-1 infection more closely, with persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges/perivascular spaces of the rodent brain (Boska, Dash, 2014, Epstein, Narayanasamy, 2013). The Tg rat on the other hand reflects chronic viral protein toxicity (Midde et al, 2011, Peng, Vigorito, 2010, Royal, Zhang, 2012, Vigorito et al, 2015, Wayman et al, 2015), and is closer pathologically to optimally-treated HIV+ patients than actively infected patients, as described below.…”

“…It has been previously suggested that the Tg rat can be a model for treated rather than untreated HIV+ patients (Abbondanzo and Chang, 2014, Moran, Booze, 2013a, Moran et al, 2014, Moran, Booze, 2013b, Nemeth et al, 2014, Peng, Vigorito, 2010, Vigorito, Connaghan, 2015). The current study concurs with this suggestion, since in more recent publications examining the neuropathology in treated HIV+ patients, the classic signs of inflammation damage such as multinucleated giant cells and HIV encephalitis were lacking.…”

Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV

“…This implies a complex pre and post synaptic dopaminergic dysfunction in the Tg rats, which we presume is related to chronic neurotoxicity associated with exposure to viral proteins [12, 17, 29, 30]. In the longitudinal component, although decreased [18F]-FP-CMT biding was seen in the WT rats, consistent with age-related degenerative changes, a more marked decrease in binding was noted in the Tg rats, suggesting an additional effect of the transgene, again likely related to chronic exposure to viral proteins.…”

“…Dopaminergic dysfunction has also been described [9–13] in the HIV-1 transgenic rat (Tg), a non-infectious Tg rat model which expresses 7 of the 9 HIV-1 viral proteins including gp120, nef, and Tat and is known to develop clinically relevant neuropathologies [14] and cognitive deficits [9, 10, 15–17]. Using [18F]-Fallypride, a PET radiotracer targeting D2/D3 receptors (D2DR and D3DR), we previously described deficits in D2/D3 striatal receptors in the Tg rat, considered to be a model of treated HIV+ patients [17, 18]. …”