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The Dual Role of HIV-1 gp120 V3 Loop-Induced Autophagy in the Survival and Apoptosis of the Primary Rat Hippocampal Neurons

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Abstract

HIV-1 gp120, an important subunit of the envelope spikes that decorate the surface of virions, is known to play a vital role in neuronal injury during HIV-1-associated neurocognitive disorder (HAND), although the pathological mechanism is not fully understood. Our previous studies have suggested that the V3 loop of HIV-1 gp120 (HIV-1 gp120 V3 loop) can induce neuronal apoptosis in the hippocampus, resulting in impairment in spatial learning and memory in Sprague–Dawley (SD) rats. In this study, we demonstrated that autophagy was significantly increased in rat primary hippocampal neurons in response to treatment of HIV-1 gp120 V3 loop. Importantly, HIV-1 gp120 V3 loop-induced autophagy played a dual role in the cell survival and death. An increase in autophagy for a short period inhibited apoptosis of neurons, while persistent autophagy over an extended period of time played a detrimental role by augmenting the apoptotic cascade in rat primary hippocampal neurons. In addition, we found that the HIV-1 gp120 V3 loop induced autophagy via AMPK/mTOR-dependent and calpain/mTOR-independent pathways, and the ERK/mTOR pathway plays a partial role. These findings provide evidence that HIV-1-induced autophagy plays a dual role in the survival and apoptosis of the primary rat hippocampal neurons and persistent autophagy may contribute to the pathogenesis of HAND, and autophagy modulation may represent a potential therapeutic strategy for reducing neuronal damage in HAND.

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Abbreviations

HIV-1:

Human immunodeficiency virus type 1

HAND:

HIV-1- associated neurocognitive disorders

GAPDH:

Glyceraldehyde-3-phosphatedehydrogenase

mTOR:

Mechanistic target of rapamycin

mTORC1:

mTOR complex 1

MAP1LC3 (LC3):

Microtubule-associated protein 1 light chain 3

ATG:

Autophagy-related gene

SQSTM1 (p62):

Sequestosome 1 (a ubiquitin-binding scaffold protein)

MAPK1 (ERK2):

Mitogen-activated protein kinase 1

MAPK3 (ERK1):

Mitogen-activated protein kinase 3

LC3B-I:

Unlipidated form of LC3B

LC3B-II:

Phosphatidylethanolamine-conjugated form of LC3B

Cas-3:

Caspase 3

3-MA:

3-Methyladenine

AMPK:

AMP activated protein kinase

MDC:

Monodansylcadaverine

NMDA:

N-Methyl-d-Aspartate

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

This work was supported by Grants from the National Natural Science Foundation of China (81171134 and 81471235), Guangdong Provincial Natural Science Foundation of China (2014A030313360), the Program of Introducing Talents of Discipline to Universities (B14036), the Science and Technology Foundation of Guangdong (2010B030700016), and the cultivation and innovation fund of Jinan University (No. 21617460).

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Author notes

  1. Sisi Liu, Yanyan Xing and Junbing Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China

    Sisi Liu, Yanyan Xing, Junbing Wang, Guangming Li, Haijie Tang, Guiling Chen, Liang Yan, Luyan Guo, Mingliang Jiang, Zheng Gong, Liqing Lin & Jun Dong

  2. Department of Orthopedics, The First Affiliated Hospital, Medical College of Jinan University, Guangzhou, Guangdong Province, China

    Rui Pan

  3. Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China

    Liqing Lin & Jun Dong

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  1. Sisi Liu
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Correspondence to Jun Dong.

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Liu, S., Xing, Y., Wang, J. et al. The Dual Role of HIV-1 gp120 V3 Loop-Induced Autophagy in the Survival and Apoptosis of the Primary Rat Hippocampal Neurons. Neurochem Res 44, 1636–1652 (2019). https://doi.org/10.1007/s11064-019-02788-3

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