Neurotoxicity of HIV-1 Tat is attributed to its penetrating property

Xiaoli Tang,Bharat Ramratnam,Huafei Lu

doi:10.1038/s41598-020-70950-x

Xiaoli Tang, Bharat Ramratnam + Show 1 more

Open Access

https://doi.org/10.1038/s41598-020-70950-x

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Journal: Scientific Reports	Publication Date: Aug 19, 2020
Citations: 12	License type: open-access

Affiliation: Brown University, Rhode Island Hospital

Abstract

We have recently engineered an exosomal Tat (Exo-Tat) which can activate latent HIV-1 in resting CD4+ T lymphocytes from antiretroviral treated HIV-1 infected patients. HIV-1 Tat protein can penetrate cell membrane freely and secrete into extracellular medium. Exo-Tat loses this penetrating property. HIV-1 Tat protein can damage the synaptic membranes contributing to the development of dementia in HIV-1 infected patients. To investigate whether the penetrating property attributes to synaptic damage in vivo, we have generated adeno-associated viruses AAV-Tat and AAV-Exo-Tat viruses. Vehicle control or AAV viruses (1 × 1012 GC/mouse in 200 μl PBS) were injected into Balb/cj mice via tail veins. The mRNA and protein expression levels in blood, brain, heart, intestine, kidney, liver, lung, muscle and spleen were determined on day 21. Intravenously injected AAV-Tat or AAV-Exo-Tat mainly infects liver and heart. Short-term expression of Tat or Exo-Tat doesn’t change the expression levels of neuronal cytoskeletal marker β3-tubulin and synaptic marker postsynaptic density 95 protein (PSD-95). Wild-type Tat, but not Exo-Tat, reduces the expression level of synaptic marker synaptophysin significantly in mice, indicating that penetrating property of HIV-1 Tat protein attributes to synaptic damage.

Highlights

We have recently engineered an exosomal Tat (Exo-Tat) which can activate latent HIV-1 in resting CD4+ T lymphocytes from antiretroviral treated HIV-1 infected patients
Exosomes loaded with HIV-1 Tat protein activate latent HIV-1 in primary, resting CD4+ T cells from Combination antiretroviral therapy (cART)-treated HIV-1-infected p atients[10]
We reasoned if the cells in human body can generate exosomes containing Tat protein, these Tat exosomes may activate latent HIV-1 from the reservoirs of HIV-1 infected patients

Summary

Introduction

We have recently engineered an exosomal Tat (Exo-Tat) which can activate latent HIV-1 in resting CD4+ T lymphocytes from antiretroviral treated HIV-1 infected patients. Wild-type Tat, but not Exo-Tat, reduces the expression level of synaptic marker synaptophysin significantly in mice, indicating that penetrating property of HIV-1 Tat protein attributes to synaptic damage. Chronic low-level expression of HIV-1 Tat protein in mice can damage the synapses demonstrating reduction of expression levels of neuroskeletal and/or synaptic markers such as the neuronal specific cytoskeletal protein βIII-Tubulin, the presynaptic vesicle protein p38 (Synaptophysin) and the postsynaptic density 95 protein (PSD-95)[13]. We have engineered an exosomal Tat which avoids its immunogenicity and can activate latent HIV-1 in primary, resting CD4+ lymphocytes from cART-treated HIV-1 infected patients[10]. We compare the short-term neurotoxicity of wild-type Tat and engineered Exo-Tat in Balb/cj mice, commonly used and readily available regular mice

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Conclusion