Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model

Abstract

HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms.

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

“…The results found, in this study, for effects of Tat expression differ from what has been described regarding, for example, inflammatory genes, both in vitro and in vivo [29,93,94], and including this mouse model [18,33]. Gliosis and neurological changes that have been reported in Tat transgenic animals, however, could result from post-transcriptional effects in models that do not involve drug abuse interactions [33]. Hypothetically, Meth sensitization could induce cis-regulatory repression elements, in addition to decreasing the expression of translation initiation complexes, such as the eIF2, eIF4, and p70S6K signaling pathways, which were identified here as presenting significant disruptions in Meth.…”

“…Nevertheless, it had an anti-directional and potentially positive impact in the context of interaction with Meth exposure. The results found, in this study, for effects of Tat expression differ from what has been described regarding, for example, inflammatory genes, both in vitro and in vivo [29,93,94], and including this mouse model [18,33]. Gliosis and neurological changes that have been reported in Tat transgenic animals, however, could result from post-transcriptional effects in models that do not involve drug abuse interactions [33].…”

HIV-1 Tat Length: Comparative and Functional Considerations

“…To our knowledge, there are no transgenic animal models that express Tat 101 (Soontornniyomkij et al, 2016;Langford et al, 2018;Green et al, 2019). The iTat model, which expresses Tat in a doxycycline-dependent manner that models chronic exposure, is a widely utilized model of HAND, however, it also does not express the Tat 101 protein (Fan et al, 2016;Langford et al, 2018).…”

“…To our knowledge, there are no transgenic animal models that express Tat 101 (Soontornniyomkij et al, 2016;Langford et al, 2018;Green et al, 2019). The iTat model, which expresses Tat in a doxycycline-dependent manner that models chronic exposure, is a widely utilized model of HAND, however, it also does not express the Tat 101 protein (Fan et al, 2016;Langford et al, 2018). Similarly, the rtTA-Tat mouse model also expresses Tat 86 under the control of a glial fibrillary acidic protein (GFAP) promoter, which has resulted in low levels of chronic inflammation (Bruce-Keller et al, 2008;Dickens et al, 2017).…”

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

“…Langford et al (Langford et al 2017) provide a review of the creation of a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mice (iTat) to understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection. Tat expression levels in the brains of iTat mice were in the physiologically relevant range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation.…”