Innate Immune Activation by cGMP-AMP Nanoparticles Leads to Potent and Long-Acting Antiretroviral Response against HIV-1

Aroh, Chukwuemika; Wang, Zhaohui; Dobbs, Nicole; Luo, Min; Chen, Zhijian; Gao, Jinming; Yan, Nan

doi:10.4049/jimmunol.1700972

Cited by 40 publications

(35 citation statements)

References 25 publications

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“…Recently, it was shown that the cytosolic DNA sensor cGAS is also implicated in sensing HIV-1 infection in activated CD4 + T cells [41]. Further characterization has indicated that productive infection, particularly proviral DNA integration, is required for cGAS-dependent DNA sensing in activated CD4 + T cells [41,87]. Additionally, IFI16 has been reported to act as a specific sensor, detecting abortive HIV-1 reverse transcripts to invoke caspase-1 activation and pyroptosis in tonsillar lymphoid CD4 + T cells abortively infected with HIV, as previously described [43].…”

Section: Innate Immune Response To Hiv-1 Infection In Cd4 + T Cellsmentioning

confidence: 99%

Sensor Sensibility—HIV-1 and the Innate Immune Response

Yin

Langer

Zhang

et al. 2020

Cells

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Innate immunity represents the human immune system’s first line of defense against a pathogenic intruder and is initiated by the recognition of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) by specialized cellular sensors, called pattern recognition receptors (PRRs). Human immunodeficiency virus type 1 (HIV-1) is a unique human RNA virus that causes acquired immunodeficiency syndrome (AIDS) in infected individuals. During the replication cycle, HIV-1 undergoes reverse transcription of its RNA genome and integrates the resulting DNA into the human genome. Subsequently, transcription of the integrated provirus results in production of new virions and spreading infection of the virus. Throughout the viral replication cycle, numerous nucleic acid derived PAMPs can be recognized by a diverse set of innate immune sensors in infected cells. However, HIV-1 has evolved efficient strategies to evade or counteract this immune surveillance and the downstream responses. Understanding the molecular underpinnings of the concerted actions of the innate immune system, as well as the corresponding viral evasion mechanisms during infection, is critical to understanding HIV-1 transmission and pathogenesis, and may provide important guidance for the design of appropriate adjuvant and vaccine strategies. Here, we summarize current knowledge of the molecular basis for sensing HIV-1 in human cells, including CD4+ T cells, dendritic cells, and macrophages. Furthermore, we discuss the underlying mechanisms by which innate sensing is regulated, and describe the strategies developed by HIV-1 to evade sensing and immune responses.

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Section: Innate Immune Response To Hiv-1 Infection In Cd4 + T Cellsmentioning

confidence: 99%

Sensor Sensibility—HIV-1 and the Innate Immune Response

Yin

Langer

Zhang

et al. 2020

Cells

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“…Immunization in knockout mice found that the adjuvant effect of the PC7A NPs is dependent on the STING pathway, although the exact mechanism remains to be determined. Considering the effects above, the Gao group cooperated with Yan et al to load 2′,3′‐cGAMP into PC7A NPs, which were used against HIV‐1 infection . The 2′,3′‐cGAMP‐loaded PC7A NPs efficiently inhibited the replication of HIV RNA and generated a long‐lasting antiretroviral response in human peripheral blood mononuclear cells, with free cGAMP as a control.…”

Section: Sting Agonistsmentioning

confidence: 99%

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

Zhao

et al. 2019

Medicinal Research Reviews

110

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Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunotherapy for cancer or other diseases. However, the negative charges, hydrophilicity, and instability of CDNs have hindered their further applications. In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction.Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. The past several years, especially 2018, has seen increasingly rapid advances in this field. Here, this review summarizes the synthesis and modification of CDNs, the identification of nonnucleotide agonists, the recent progress in delivery systems and the medical applications, such as personalized vaccine adjuvants, in detail. In addition, in this review, we summarize the STING inhibitors' advances from two aspects, covalent, and noncovalent inhibitors. K E Y W O R D S agonist, cyclic dinucleotides, immunotherapy, inhibitor, STING

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“…134 Hence, delivery of exogenous type I IFN, cGAMP, or STING agonists elicited a long-lasting immune response against HIV-1, suggesting a potential new therapeutic concept. 133,135 On the other hand, Gram et al revealed that the failure of B-cells in producing type I IFN is not reversed by Epstein-Barr virus-induced STING expression in B-cells. 134 This suggests there might be one or more players in the DNA-sensing pathways that are yet to be discovered.…”

Section: A Antimicrobial Immunitymentioning

confidence: 99%

Sensing Self and Non-Self DNA by Innate Immune Receptors and Their Signaling Pathways

Sok¹,

Ori²,

Nagoor³

et al. 2018

Crit Rev Immunol

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The innate immune system serves as the first line of defense to protect the host from pathogen infection. As a first step, the pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs), such as non-self DNA derived from pathogens, and damage-associated molecular patterns (DAMPs), such as self DNA released from damaged or injured cells. Sensing of such DNAs elicits innate immune responses through the production of type I interferons (IFNs) and proinflammatory cytokines resulting from the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB), respectively. These cytokines are key players in interlinking innate and adaptive immune responses. However, defects in DNA sensors and their signaling cascades lead to dysregulation of immune responses, autoimmune diseases, and cancer progression. Here we provide an update on DNA signaling pathways in response to pathogen infection and cell injury, and on the roles of regulators in governing the immune system and maintaining host homeostasis. We also discuss the evasion of immunosurveillance by pathogens.

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Innate Immune Activation by cGMP-AMP Nanoparticles Leads to Potent and Long-Acting Antiretroviral Response against HIV-1

Cited by 40 publications

References 25 publications

Sensor Sensibility—HIV-1 and the Innate Immune Response

Sensor Sensibility—HIV-1 and the Innate Immune Response

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

Sensing Self and Non-Self DNA by Innate Immune Receptors and Their Signaling Pathways

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