HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

Abstract

HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here, we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr-dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.

Aberrant development of excitatory circuits to inhibitory neurons in the primary visual cortex after neonatal binocular enucleation

“…It is still unknown how much of the activity in V1 is changed at P16/17 after neonatal enucleation. In adult mice, after losing retinal input, neural activity in V1 rapidly decreases, recovering within 72 h due to homeostatic plasticity 70 , 84 . However, the activity in cortical inhibitory neurons does not recover within 72 h 85 , suggesting a compensatory decrease of cortical inhibition to decreased activity from retina.…”

How SARS-CoV-2 and Other Viruses Build an Invasion Route to Hijack the Host Nucleocytoplasmic Trafficking System

“…HIV Vpr suppresses the host antiviral response by interacting with α-importins (preferentially α5, but also, to a lesser extent, α1 and α4) to inhibit the IRF3 activation and to block the nuclear import of IRF3 and NfκB [155]. HIV Vpr has an N-terminal NLS and a C-terminal NLS [156].…”

Dodging the Host Interferon-Stimulated Gene Mediated Innate Immunity by HIV-1: A Brief Update on Intrinsic Mechanisms and Counter-Mechanisms

“…They further showed that Vpr localized to the nuclear pore complex, prevented the interaction of karyopherins with IRF3 and NFκB, which is required for their transport into the nucleus. Subsequently, this immune inhibitory mechanism by Vpr was shown to be dependent on the cofactor DCAF1, a substrate receptor of Cullin-4 RING E3-Ubiquitin ligase (CRL4) ( 55 ). While most transcription factors are degraded by HIV proteins, Vpu stabilises host ISGs such as p53 that leads the host cell towards apoptosis in the late stage of infection ( 83 ).…”