Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

Liu, Cheng; Yu, Haisheng; Li, Guangming; Li, Feng; Ma, Jianping; Li, Jingyun; Chi, Liqun; Zhang, Liguo; Su, Lishan

doi:10.1172/jci.insight.94366

Cited by 76 publications

(82 citation statements)

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“…We show that lower doses of type I IFNs (300 units) produce clear MAPK signaling activation in DRG neurons in vitro and in vivo . The dose used in our experiments is consistent with earlier studies examining dose-dependent effects of type I IFN signaling on what are now known as canonical signaling pathways (Larner et al, 1986; Hilkens et al, 2003) and with plasma levels induced by virus (Gerlach et al, 2006; Murray et al, 2015; Cheng et al, 2017) or poly (I:C) (Shibamiya et al, 2009).…”

Section: Discussionsupporting

confidence: 87%

“…We first sought to investigate the nociceptive responses produced by type I interferons (α and β) in vivo in both sexes. The dose (300 units (U) – approximately 5 ng) of IFNs was chosen based on previous studies showing concentration-dependent effects on cellular signaling pathways (Larner et al, 1986; Hilkens et al, 2003) and studies showing plasma levels of type I IFNs in mice in response to viral infection (~ 1-2 ng/ml) (Gerlach et al, 2006; Shibamiya et al, 2009; Murray et al, 2015; Cheng et al, 2017). In male mice, intraplantar (i.pl.)…”

Section: Resultsmentioning

confidence: 99%

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Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Barragán-Iglesias¹,

Franco-Enzástiga

Jeevakumar³

et al. 2019

Preprint

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“…S6C, and see Methods). Strikingly, IFN- α and IFN- γ are predicted drivers of these sustained responses for all five cell types even though these modules do not contain the typical ISGs; in chronic HIV infection, prolonged IFN-I stimulation has been shown to maintain viral suppression but also blunt other immune functions in a humanized mouse model 65,66 . Matching Luminex data confirmed elevated levels of IP-10 and MIG at one-month post HIV detection (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2D). While known to be a key factor in controlling HIV replication 30,65 and the major response in NHP SIV infection models 52,90 , the timing of response and extent to which it pervades all peripheral cell subsets in humans has not yet been described. Of note, both controllers (P3 & P4) exhibited interferon response modules the week before peak viremia, consistent with the faster resolution of interferon response in natural SIV hosts compared to non-natural hosts 46–49 .…”

Section: Discussionmentioning

confidence: 99%

Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection

Kazer

Aicher

Muema

et al. 2019

Preprint

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30Cellular immunity is critical for controlling intracellular pathogens, but the dynamics and 31 cooperativity of the evolving host response to infection are not well defined. Here, we apply single-32 cell RNA-sequencing to longitudinally profile pre-and immediately post-HIV infection peripheral 33 immune responses of multiple cell types in four untreated individuals. Onset of viremia induces a 34 strong transcriptional interferon response integrated across most cell types, with subsequent pro-35 inflammatory T cell differentiation, monocyte MHC-II upregulation, and cytolytic killing. With 36 longitudinal sampling, we nominate key intra-and extracellular drivers that induce these 37 programs, and assign their multi-cellular targets, temporal ordering, and duration in acute 38 infection. Two individuals studied developed spontaneous viral control, associated with initial 39 elevated frequencies of proliferating cytotoxic cells, inclusive of a previously unappreciated 40 proliferating natural killer (NK) cell subset. Our study presents a unified framework for 41 characterizing immune evolution during a persistent human viral infection at single-cell resolution, 42 and highlights programs that may drive response coordination and influence clinical trajectory. 43 44 54Recently, high-throughput single-cell RNA-sequencing (scRNA-Seq) has emerged as a 55 powerful tool to characterize, transcriptome-wide, complex human systems in health and disease 56 at single-cell resolution [3][4][5][6][7][8][9] . When applied to a collection of samples across a disease setting, this 57 approach provides a platform for investigating cell types, states, interactions, and drivers 58 associated with that disease; this information can be used to develop testable hypotheses on 59 therapeutic modulations that may ameliorate disease state 7,8 . Meanwhile, within an individual, 60longitudinal sampling provides an opportunity to decipher, at unprecedented resolution and 61 absent potentially confounding inter-individual variability 7 , shifts in these same variables, and to 62 3 associate observed changes with internal or external perturbations 10-12 . Such sampling of a host's 63 exposure to a pathogen could provide foundational insights into essential cellular response 64 features and their coordination, empowering the rational design of improved prophylactic 65 interventions. 66Illustratively, a better understanding of the interplay between innate and adaptive immune 67 responses at the very earliest stages of a viral infection, and its impact on long-term disease, 68 could reveal principles to accelerate prevention efforts. Human Immunodeficiency Virus (HIV) has 69 been the subject of thorough study, and thus is a well-considered model system for examining 70 host responses to a pathogen. Moreover, although the development of antiretroviral therapy 71 (ART) 13 , as well as implementation of pre-exposure prophylaxis (PrEP) 14 and combination 72 prevention efforts, has improved the lives of persons living with HIV, increased life expectancie...

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“…[20–22]. Even though the exact role of IFNs in HIV infection is still under debate, beneficial implications of IFNα as suppressed viral load, increased NK cell function and enhanced suppressive capacity of CD8 + T cells as well as an increase in the expression of ISGs containing HIV restriction factors and thus hindering viral transmission and replication could be observed [23–25]. On the other hand, rescued CD4 + T cell depletion and restored cell function following blockade of IFNAR was reported [23,26], as well as systemic immune activation and limited antigen-specific T cell responses [24], thus indicating a potential detrimental influence of IFN on the course of HIV infection.…”

Section: Introductionmentioning

confidence: 99%

HIV infection does not alter Interferon α/β receptor expression on mucosal immune cells

Ickler

Francois

Widera

et al. 2019

Preprint

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Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

Cited by 76 publications

References 50 publications

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection

HIV infection does not alter Interferon α/β receptor expression on mucosal immune cells

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