Unperturbed posttranscriptional regulatory Rev protein function and HIV-1 replication in astrocytes.

Ashok Chauhan,Giovanni Maga

doi:10.1371/journal.pone.0106910

Abstract

Astrocytes protect neurons, but also evoke proinflammatory responses to injury and viral infections, including HIV. There is a prevailing notion that HIV-1 Rev protein function in astrocytes is perturbed, leading to restricted viral replication. In earlier studies, our finding of restricted viral entry into astrocytes led us to investigate whether there are any intracellular restrictions, including crippled Rev function, in astrocytes. Despite barely detectable levels of DDX3 (Rev-supporting RNA helicase) and TRBP (anti-PKR) in primary astrocytes compared to astrocytic cells, Rev function was unperturbed in wild-type, but not DDX3-ablated astrocytes. As in permissive cells, after HIV-1 entry bypass in astrocytes, viral-encoded Tat and Rev proteins had robust regulatory activities, leading to efficient viral replication. Productive HIV-1 infection in astrocytes persisted for several weeks. Our findings on HIV-1 entry bypass in astrocytes demonstrated that the intracellular environment is conducive to viral replication and that Tat and Rev functions are unperturbed.

Highlights

Astrocytes are neuroprotective cells in the brain that are important in HIV-1-mediated neuropathology, serving as inflammatory cells in response to viral products
RNA helicases, including DDX3, Tar RNA binding protein (TRBP) [26,29,52], Sam68 [52,53,54,55,56], and hematopoietic cell-specific Lyn substrate 1-associated protein X-1 (Hax-1) [57] in HIV permissive cells have been described as mediators of viral replication and RNA transport [24,58], we investigated whether DDX3 and TRBP in astrocytes are involved in Rev function and HIV replication
Highly productive HIV-1 infection occurred in Jurkat cells (Fig. 1B), but minimal infection by recombinant NLENY1 or wild-type NL4-3 viruses was observed in astrocytes (HFA and SVGA) (Fig. 1B, C)

Summary

Introduction

Astrocytes are neuroprotective cells in the brain that are important in HIV-1-mediated neuropathology, serving as inflammatory cells in response to viral products. In HIV-1-infected brain tissues, up to 19% of astrocytes carry viral DNA [1,2,3]. Restrictions at the HIV-1 entry level in astrocytes have been reported [4,5,6,7,8], and have suggested a compensatory viral entry mechanism [7,8]. Some studies have suggested that there are intracellular restrictions on HIV-1 replication in astrocytes [9], with the presence of efficient early viral transcripts, but low levels of late transcripts being responsible for structural proteins [9]. Among them Src-associated substrate in mitosis (Sam68), Tar RNA binding protein (TRBP), and protein kinase RNA-activated (PKR), have been implicated in unproductive HIV infection in astrocytes

Methods

Results

Conclusion