Nef-induced CCL2 Expression Contributes to HIV/SIV Brain Invasion and Neuronal Dysfunction.

Michael H Lehmann,Jonas M Lehmann,Volker Erfle

doi:10.3389/fimmu.2019.02447

Abstract

C-C motif chemokine ligand 2 (CCL2) is a chemoattractant for leukocytes including monocytes, T cells, and natural killer cells and it plays an important role in maintaining the integrity and function of the brain. However, there is accumulating evidence that many neurological diseases are attributable to a dysregulation of CCL2 expression. Acquired immune deficiency syndrome (AIDS) encephalopathy is a severe and frequent complication in individuals infected with the human immunodeficiency virus (HIV) or the simian immunodeficiency virus (SIV). The HIV and SIV Nef protein, a progression factor in AIDS pathology, can be transferred by microvesicles including exosomes and tunneling nanotubes (TNT) within the host even to uninfected cells, and Nef can induce CCL2 expression. This review focuses on findings which collectively add new insights on how Nef-induced CCL2 expression contributes to neurotropism and neurovirulence of HIV and SIV and elucidates why adjuvant targeting of CCL2 could be a therapeutic option for HIV-infected persons.

Highlights

Acquired immune deficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV) [1, 2], has to date resulted in the deaths of over 32 million people
The findings summarized here classify HIV/SIV Nef-induced CCL2 expression in the complex pathogenesis of HIV-associated neurocognitive disorders (HAND), and once again highlight the special role which the CCL2-CCR2 axis can play in a neurological disease
Drugs which have been developed to target this chemokine or its receptor could be an option for an adjuvant therapy in HIV-infected persons

Summary

INTRODUCTION

Acquired immune deficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV) [1, 2], has to date resulted in the deaths of over 32 million people. The findings collectively result in a model in which Nef-containing PBMCs and extracellular vesicles carrying Nef attach to and transfer Nef into endothelial cells, leading to CCL2 production that can cause BBB leakiness and subsequent entry of HIV/SIV by infected cells into the brain (Figure 1). Of note, this provides a simple explanation of why SIV with a deleted nef gene cannot enter the brain [43]. CCL2 is major mediator of pain [137], and chronic pain is a common burden in people living with HIV/AIDS [138]

SUMMARY

CONCLUSION