A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1

Abstract

Background: HIV-1 infection remains a major public health concern despite effective combination antiretroviral therapy (cART). The virus enters the central nervous system (CNS) early in infection and continues to cause HIVassociated neurocognitive disorders (HAND). The pathogenic mechanisms of HIV-associated brain injury remain incompletely understood. Since HIV-1 activates the type I interferon system, which signals via interferon-α receptor (IFNAR) 1 and 2, this study investigated the potential role of IFNAR1 in HIV-induced neurotoxicity. Methods: We cross-bred HIVgp120-transgenic (tg) and IFNAR1 knockout (IFNAR1KO) mice. At 11-14 months of age, we performed a behavioral assessment and subsequently analyzed neuropathological alterations using deconvolution and quantitative immunofluorescence microscopy, quantitative RT-PCR, and bioinformatics. Western blotting of brain lysates and an in vitro neurotoxicity assay were employed for analysis of cellular signaling pathways. Results: We show that IFNAR1KO results in partial, sex-dependent protection from neuronal injury and behavioral deficits in a transgenic model of HIV-induced brain injury. The IFNAR1KO rescues spatial memory and ameliorates loss of presynaptic terminals preferentially in female HIVgp120tg mice. Similarly, expression of genes involved in neurotransmission reveals sex-dependent effects of IFNAR1KO and HIVgp120. In contrast, IFNAR1-deficiency, independent of sex, limits damage to neuronal dendrites, microgliosis, and activation of p38 MAPK and restores ERK activity in the HIVgp120tg brain. In vitro, inhibition of p38 MAPK abrogates neurotoxicity caused similarly by blockade of ERK kinase and HIVgp120. Conclusion: Our findings indicate that IFNAR1 plays a pivotal role in both sex-dependent and independent processes of neuronal injury and behavioral impairment triggered by HIV-1.

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

“…Notably, HIV-1 proteins, Vpu and Nef, inhibit ISG expression through canonical IFNa mediated JAK/STAT1 signaling, blocking any antiviral benefits from IFNa (116). Knockout of IFNAR1 in an HIV-induced brain injury mouse model provided memory benefits and neuronal injury protection while suppressing p38 activation, indicating involvement of type I IFN non-canonical signaling in HIV-1-related neurotoxicity (117). Indeed, there is accumulating evidence that sustained type I IFN signaling, surprisingly, can promote viral replication for a number of viruses, mediated by induction of certain ISGs and inhibition of IRFs (14).…”

Arachidonic Acid Cascade and Eicosanoid Production Are Elevated While LTC4 Synthase Modulates the Lipidomics Profile in the Brain of the HIVgp120-Transgenic Mouse Model of NeuroHIV

“…Quantitative real-time polymerase chain reaction (qRT-PCR) was performed using Power PCR SYBR Green Master Mix (Thermo Fisher Scientific, cat# 4368708) and the primers listed in Table 1. QRT-PCR was performed using a QuantStudio 6 Flex system (Applied Biosystems/Life Technologies, Waltham, MA, USA) and ∆∆Ct values were calculated using the housekeeping gene GAPDH as previously described [38,44]. ANOVA analyses of male and female mice were performed independently.…”

“…Whole brain tissue was collected from a 12-month-old cohort consisting of n = 6 animals per genotype for both male and female mice. Tissues were processed as previously published with minor modifications [38,44,45]. Fifty micrograms of protein were loaded on a 4-12% SDS-PAGE gel (Invitrogen, Waltham, MA, USA) and transferred onto PVDF membrane (Invitrogen) with SeeBlue Plus2 pre-stained protein standard ladder (Invitrogen).…”

Transcriptomic and Genetic Profiling of HIV-Associated Neurocognitive Disorders

“…These pathways included the interferon response, activation of NFkB by virus, CCR5 in macrophages, and GABA receptors, among others (Maung et al, 2014). Follow up studies analyzing targeted groups of genes with quantitative reverse transcription polymerase chain reaction (qRT-PCR) arrays also verified significant changes in expression of genes related to neurotransmission (Ojeda-Juárez et al, 2020;Singh et al, 2020).…”