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Aging and disease    2020, Vol. 11 Issue (1) : 93-107     DOI: 10.14336/AD.2019.0323
Orginal Article |
Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging
Xiaojie Zhao1, Yan Fan2, Philip H. Vann2, Jessica M. Wong2, Nathalie Sumien2, Johnny J. He1,*
1Department of Microbiology, Immunology & Genetics and
2Department of Pharmacology & Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
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HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. HIV Tat protein is known to be a major pathogenic factor for HIV/neuroAIDS through a myriad of direct and indirect mechanisms. However, most, if not all of studies involve short-time exposure of recombinant Tat protein in vitro or short-term Tat expression in vivo. In this study, we took advantage of the doxycycline-inducible brain-specific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Long-term Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation. There were sex- and brain region-dependent differences in behaviors, pathologies, and epigenetic changes resulting from long-term Tat expression. All these changes are reminiscent of accelerated aging, raising the possibility that HIV Tat contributes, at least in part, to HIV infection-associated accelerated aging in HIV-infected individuals. These findings also suggest another utility of this model for HIV infection-associated accelerated aging studies.

Keywords HIV-1 Tat      accelerated aging      DNA methyltransferases      DNA methylation     
Corresponding Authors: Johnny J. He   
About author:

These authors contributed equally to this work.

Just Accepted Date: 11 April 2019   Issue Date: 15 January 2020
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Xiaojie Zhao
Yan Fan
Philip H. Vann
Jessica M. Wong
Nathalie Sumien
Johnny J. He
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Xiaojie Zhao,Yan Fan,Philip H. Vann, et al. Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging[J]. Aging and disease, 2020, 11(1): 93-107.
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Figure 1.  Spatial memory of iTat mice by Morris water maze (MWZ). Wild-type (Wt) and iTat mice of 21 days old were fed with Dox-containing food pellets for 12 months and their short- and long-term spatial memory were determined. (A) Scheme of MWZ test. Mice underwent pre-training for 2 days, then training every day and probe test (marked by thin arrows) every other day, and the data in last probe test (Day 13) was analyzed to determine short-term spatial memory. After 7 days, the mice underwent another probe test (marked by a thick arrow) on day 18 to determine long-term spatial memory. (B and C) iTat short-term spatial memory (B) and long-term spatial memory (C). Mice were grouped into males and females and assessed for spatial memory based on the Time at target quadrant % (I), Distance to target quadrant (II), Time at platform site % (III), Distance in platform site (IV), Platform entries (V), and Speed (VI). The number of mice in each group was shown in the bar.
Figure 2.  Locomotor activity of iTat mice by open field test. The mice were placed into an open chamber and their movement was recorded for 10 min. The trace was analyzed for total travel distance (A) and travel speed (B). The number of mice in each group was shown in the bar.
Figure 3.  Motor coordination and balance ability of iTat mice by bridge walk test. The mice were placed into different types of raised beams, and the latency to fall from the beam was determined. The task was carried out with increasing difficulties and in the order of large square (LS), large round (LR), small square (SS), and small round (SR). The number of mice in each group was shown in the bar.
Figure 4.  Expression of GFAP, SYP and PSD95 in the brain of iTat mice. Cortex (CORT, A), cerebellum (CERE, B), hippocampus (HIP, C) and caudate putamen (CPU, D) of the mice were dissected, homogenized for lysates, and analyzed for expression of GFAP, SYP and PSD95, by Western blotting. β-actin was used as an equal loading control. Six mice in each group were used for the analysis and three of them were randomly selected from the same SDS-PAGE for presentation. Protein expression in each group was normalized by Wt males and the relative level was shown at the right of the respective blots.
Probe test DayGenotypeSexSuccessFailureTotalp

Table 1  Latency to platform within 30s.
Figure 5.  DNA Methyltransferase expression and genomic DNA methylation in the brain of iTat mice. qPT-PCR was used to screen the mRNA expression of DNMT1 (A-I) DNMT3A (A-II) and DNMT3B (A-III) in whole brain lysates, followed by Western blots to determine DNMT3B expression in different brain regions including CORT, CERE, HIP and CPU (two close bands were recognized by DNMT3B antibody in some brain regions) (B). Next, two brain regions, CORT and CERE, were selected to elucidate the genomic DNA methylation level by 5-methylcytosine ELISA. The number of mice was shown in the bar, except for Western blots where six mice were used in every group and three were randomly selected from the same SDS-PAGE for presentation. All data was normalized by Wt males and shown as a relative level. The internal control of Western blots in (B) was β-actin which was same to figure 4 in different brain regions.
iTat vs Wt
iTat vs Wt
Male vs Female




Table 2  Summary of comparisons between different mice/sex and different brain regions.
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