Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging

Abstract

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 brainspecific 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.

Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice

“…Further, motor symptoms such as leg weakness and unsteady gait were observed in mild forms of HAND (4). In this context, the lowered ambulation observed in DOX-fed mice was consistent with previous reports measuring ambulation using same test and model (43) as well as a different HIV-1 Tat model, which measured ambulation using open field test (48). In parallel, the DOX-injected iTat mice showed similar ambulation, center time, and higher vertical activity as compared to their Treatment Time controls.…”

“…Acute Tat expression was induced using DOX injection method, similar to previous studies investigating Tat-mediated behavioral changes in iTat mice ( 36 , 38 , 39 ). Additionally, prolonged Tat expression was induced via food, which was also used in this model previously ( 43 ). Tat gene expression was quantified in mRNA isolated from iTat mouse brain tissues using one-step PCR.…”

“…HIV-1 Tat is a key protein involved in neuronal dysfunction (28,29), BBB disruption (22), oxidative stress (30,31), elevating MMPs (32,33), and possesses chemokine-like abilities that promote immune infiltration into the brain (26,34). Several investigations using HIV-1 Tat based transgenic models elucidated effects of acute Tat expression, i.e., a few days after Tat induction (35)(36)(37)(38)(39)(40)(41), while the effects of prolonged Tat expression were seldom tested until recently (42,43). It is imperative to test how duration of Tat expression alters its direct and indirect neurotoxic effects since Tat is known to be produced by infected cells during early as well as late stages, even in the presence of ART.…”

HIV-1 Tat and cocaine impact mitochondrial epigenetics: effects on DNA methylation

“…We analysed the percentage of methylation in mitochondrial regions such as ADS2886-FS2 (MT-CYB), ADS9500-FS1 (MT-RNR1), ADS2888-FS1re (D-loop), and ADS9515-FS2 (MT-ND1) using pyrosequencing assays for mtDNA, as shown in Figure 5(a) and 5(b), respectively. We found that the percentage of mtDNA methylation in HIV-1 Tat-treated astrocyte mitochondria was significantly lower at ChrM: 14,957 CpG#396 (MT-CYB), ChrM:739 CpG#19 (MT-RNR1), ChrM:624 CpG#17 (MT-RNR1), ChrM:3351 CpG#93 (MT-ND1), ChrM:121 CpG #8 (D-loop), ChrM:106 CpG #7 (D-loop) and ChrM:97 CpG #6 (D-loop) than that in untreated human primary astrocyte mitochondria, as shown in Figure 5(a) and 5(b). Cocaine-exposed human primary astrocytes showed slightly lower percentages of mtDNA methylation than control astrocytes, as shown in Figure 5(a) and 5(b).…”

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

“…In contrast, the astrocytes that are affected as a result of the bystander effect demonstrated activation of the NLRP3 inflammasome, which, in turn, was related to mitochondrial damage [ 164 ]. In the doxycycline-inducible, astrocyte-specific HIV-1 Tat transgenic mice (iTat) model, it has been reported that long-term expression of HIV-1 Tat in the brain manifested poor memory and motor function outcomes along with brain region- and gender-specific dysregulation of neuropathological changes, similar to age-related changes involving increased astrocyte activation and altered synaptic plasticity—the ability of neurons to bring about changes in the connections between neuronal networks in response to use or disuse [ 184 ]. HIV-1 infection has been shown to accelerate the biological aging process of HIV-1-infected individuals by ~five years in blood cells [ 3 ] and ~seven years in the brain [ 56 , 57 ].…”