In this competing renewal application, we will critically test a gene excision cure approach followed by neurorestoration therapy as a strategy to remove the HIV-1 provirus from the brain and promote neurocognitive recovery. Furthermore, efficacy of cure/restoration may be tailored for both males and females, as well as for those with a history of cocaine abuse. The hypothesis is that gene excision and estrogen/soy isoflavone therapy will restore neurocognitive function and synaptic complexity from the progressive decline characteristic of HIV-1 associated neurocognitive disorders (HAND). Thus, estrogenic compounds may serve as neurorestorative agents for the combined effects of cocaine/HIV proteins on producing synaptic impairments in the nucleus accumbens and prefrontal cortex, critical brain regions involved in the cognitive dysfunction associated with HAND.
The specific aims are: 1) To establish efficacious neurorestoration of HIV-1/ cocaine-induced synaptopathy. The proposed in vitro experiments will establish neurorestoration at the synaptic level following both provirus activation and HIV-1 gene excision strategies. Novel compounds will be examined for neurorestoration of HIV-1 protein induced synaptopathy following cure strategies, with and without cocaine co-exposures, in sex-specified cell cultures. 2) To establish recovery from executive function deficits in HIV-1 transgenic animals, and the role of biological sex, with gene excision/ neurorestorative therapies. The ability to restore the neurocognitive/pathological consequences of HIV-1 proteins will be determined using assessment of executive function and synaptic plasticity/dendritic spines. Investigations will focus on quantifying spine density changes with respect to regulators of nucleus accumbens medium spiny neurons and prefrontal cortical neuronal plasticity. 3) To establish neurocognitive recovery in HIV-1 Tg animals, with deficits exacerbated by a history of cocaine abuse, with gene excision/ neurorestoration therapies. A critical in vivo test of gene excision/neurorestoration therapies will be provided with HIV-1 Tg animals that have an acquired history of cocaine self-administration; cocaine may accelerate the progression of HAND in HIV-1 infected patients by disrupting frontal cortex-nucleus accumbens circuitry. The robustness and generality of neurorestoration will subsequently be tested with self-administration of other abused substances (e.g. methamphetamine and methylphenidate). We are in a unique position to establish the trajectory of neurocognitive decline and synaptodendritic loss consequent to chronic HIV-1 protein/provirus expression and critically test a gene excision/regenerative-based therapeutic approach to protect and/or restore synaptodendritic complexity and neurocognitive function.
HIV-1 infection can be controlled by antiretroviral drug therapy; however, drug therapy alone is not able to eliminate the HIV-1 virus from the brain. Neurocognitive impairments from persistent virus are a challenge for curing HIV-1. Powerful new methods have been developed which are capable of editing the HIV-1 gene from brain cells. This project will determine the limits/opportunities for HIV-1 gene removal from the nervous system of males and females, drug abusers, and means for restoring neural function. Successful completion of this project will significantly advance the field towards effective cures for HIV-1 neurocognitive impairments.
|Li, Hailong; Illenberger, Jessica M; McLaurin, Kristen A et al. (2018) Identification of Dopamine D1-Alpha Receptor Within Rodent Nucleus Accumbens by an Innovative RNA In Situ Detection Technology. J Vis Exp :|
|McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F (2018) Evolution of the HIV-1 transgenic rat: utility in assessing the progression of HIV-1-associated neurocognitive disorders. J Neurovirol 24:229-245|
|Bertrand, Sarah J; Mactutus, Charles F; Harrod, Steven B et al. (2018) HIV-1 proteins dysregulate motivational processes and dopamine circuitry. Sci Rep 8:7869|
|Mohseni Ahooyi, Taha; Shekarabi, Masoud; Torkzaban, Bahareh et al. (2018) Dysregulation of Neuronal Cholesterol Homeostasis upon Exposure to HIV-1 Tat and Cocaine Revealed by RNA-Sequencing. Sci Rep 8:16300|
|Fitting, Sylvia; McLaurin, Kristen A; Booze, Rosemarie M et al. (2018) Dose-dependent neurocognitive deficits following postnatal day 10 HIV-1 viral protein exposure: Relationship to hippocampal anatomy parameters. Int J Dev Neurosci 65:66-82|
|McLaurin, Kristen A; Li, Hailong; Booze, Rosemarie M et al. (2018) Unraveling Individual Differences In The HIV-1 Transgenic Rat: Therapeutic Efficacy Of Methylphenidate. Sci Rep 8:136|
|McLaurin, Kristen A; Moran, Landhing M; Li, Hailong et al. (2017) A Gap in Time: Extending our Knowledge of Temporal Processing Deficits in the HIV-1 Transgenic Rat. J Neuroimmune Pharmacol 12:171-179|
|McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F (2017) Selective developmental alterations in The HIV-1 transgenic rat: Opportunities for diagnosis of pediatric HIV-1. J Neurovirol 23:87-98|
|McLaurin, Kristen A; Booze, Rosemarie M; Mactutus, Charles F et al. (2017) Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat. Front Behav Neurosci 11:212|
|Javadi-Paydar, Mehrak; Roscoe Jr, Robert F; Denton, Adam R et al. (2017) HIV-1 and cocaine disrupt dopamine reuptake and medium spiny neurons in female rat striatum. PLoS One 12:e0188404|
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