Chronic low-level expression of HIV-1 Tat promotes a neurodegenerative phenotype with aging

Dickens, Alex M.; Yoo, Seung Wan; Chin, Alfred C.; Xu, Jiadi; Johnson, Tory P.; Trout, Amanda L; Hauser, Kurt F.; Haughey, Norman J.

doi:10.1038/s41598-017-07570-5

Cited by 74 publications

(63 citation statements)

References 90 publications

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“…Treatment of recombinant Tat protein and short-term (21 days) Tat expression have led to decreased PSD95 and SYP expression in vitro [59,93] and in CORT [94]. The findings from the current studies clearly show that Tatinduced neurotoxicity is brain region-and sex-dependent and suggest that long-term Tat expression could result in neuropathological changes similarly to aging-related changes in terms of GFAP, SYP and PSD95 expression in the brain.…”

Section: Discussionsupporting

confidence: 56%

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

Zhao

Fan²,

Vann³

et al. 2020

Aging and disease

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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 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.

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Section: Discussionsupporting

confidence: 56%

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

Zhao

Fan²,

Vann³

et al. 2020

Aging and disease

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“…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). These mice were observed for an entire year, leading to noticeable reductions in brain volume and alterations in synaptic and axonal damage.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Length: Comparative and Functional Considerations

et al. 2020

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“…Another limitation of this and other humanized mouse models is the fact that the remaining cells present in the brain are of murine, not human, origin. However, the critical interactions between HIV proteins like Tat and Env have been shown to act on murine brain cells and induce pathological sequelae, even in the absence of human hematopoietic cells (62)(63)(64). Finally, the overall lifespan of mice is relatively short compared with that of humans.…”

Section: Discussionmentioning

confidence: 99%

T cells establish and maintain CNS viral infection in HIV-infected humanized mice

Honeycutt

Liao

Nixon

et al. 2018

Journal of Clinical Investigation

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The human brain is an important site of HIV replication and persistence during antiretroviral therapy (ART). Direct evaluation of HIV infection in the brains of otherwise healthy individuals is not feasible; therefore, we performed a large-scale study of bone marrow/liver/thymus (BLT) humanized mice as an in vivo model to study HIV infection in the brain. Human immune cells, including CD4+ T cells and macrophages, were present throughout the BLT mouse brain. HIV DNA, HIV RNA, and/or p24+ cells were observed in the brains of HIV-infected animals, regardless of the HIV isolate used. HIV infection resulted in decreased numbers of CD4+ T cells, increased numbers of CD8+ T cells, and a decreased CD4+/CD8+ T cell ratio in the brain. Using humanized T cell-only mice (ToM), we demonstrated that T cells establish and maintain HIV infection of the brain in the complete absence of human myeloid cells. HIV infection of ToM resulted in CD4+ T cell depletion and a reduced CD4+/CD8+ T cell ratio. ART significantly reduced HIV levels in the BLT mouse brain, and the immune cell populations present were indistinguishable from those of uninfected controls, which demonstrated the effectiveness of ART in controlling HIV replication in the CNS and returning cellular homeostasis to a pre-HIV state.

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Chronic low-level expression of HIV-1 Tat promotes a neurodegenerative phenotype with aging

Cited by 74 publications

References 90 publications

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

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

HIV-1 Tat Length: Comparative and Functional Considerations

T cells establish and maintain CNS viral infection in HIV-infected humanized mice

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