HIV-1 intron-containing RNA expression induces innate immune activation and T cell dysfunction

Akiyama, Hisashi; Miller, Caitlin M.; Ettinger, Chelsea R.; Belkina, Anna C.; Snyder‐Cappione, Jennifer; Gummuluru, Suryaram

doi:10.1038/s41467-018-05899-7

Cited by 69 publications

(116 citation statements)

References 57 publications

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“…With the progress of the disease, despite the efforts of T cells to ght against the virus, CD4, CD8 and other lymphocytes are reduced in severe patients or in the later stage of the disease due to the virulence of the virus or the decline of the body's immunity. Possible, the mechanism is similar to that of CD4 cell reduction caused by HIV [26,27]. These results re ect the body reach the maximum to clear the virus, so that this stage may result in decreased lung function, liver function, kidney function, and even blood clotting and heart function.…”

Section: Discussionmentioning

confidence: 69%

Clinical Characteristics and CT Manifestations of 143 Patients With 2019 Novel Coronavirus Disease (COVID-19) in Taizhou City, Zhejiang, China

Kuang

Lin

et al. 2020

Preprint

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Background In December 2019, the first case of pneumonia associated with the SARS-CoV-2 was found in Wuhan and rapidly spread throughout China, so data are needed on the affected patients. The purpose of our study was to find the clinical manifestations and CT features of COVID-19.Methods All patients with COVID-19 in Taizhou city were retrospectively included and divided into non-severe group and severe group according to the severity of the disease. The clinical manifestations, laboratory examinations and imaging features of COVID-19 patients were analyzed, and the differences between the two groups were compared.Results A total of 143 laboratory-confirmed cases were included in the study, including 110 non-severe patients and 33 severe patients. The median age of patients was 47 (range 4–86 years). Fever (73.4%) and cough (63.6%) were the most common initial clinical symptoms. Between two groups of cases, the results of aspartate transaminase, creatine kinase and lactate dehydrogenase, serum albumin, CPR, glomerular filtration rate, amyloid protein A, fibrinogen, calcitonin level and oxygen partial pressure, red protein, IL – 10, absolute value of CD3, CD4, CD8 were different, and the difference was statistically significant (P < 0.05). On admission, the CT showed that the lesions were mostly distributed in the external lung or under the pleura (135 cases (98%)), and most of lesions presented as patchy (81%), heterogeneous (73%) and mixed density (63%) shadow. Consolidation (68% vs 41%), bronchial inflation signs (59% vs 41%), and bronchiectasis (71% vs 39%) were more common in the severe group.Conclusions Most of the cases of COVID-19 in Taizhou have mild symptoms and no death. In addition to clinical symptoms, some laboratory tests (such as absolute values of CD4 and CD8) and CT findings can be used to assess the severity of the disease.

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Section: Discussionmentioning

confidence: 69%

Clinical Characteristics and CT Manifestations of 143 Patients With 2019 Novel Coronavirus Disease (COVID-19) in Taizhou City, Zhejiang, China

Kuang

Lin

et al. 2020

Preprint

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“…There is a reported connection between harboring latent HIV and IR expression on T cells: CD4+ T cells from virally suppressed HIV+ subjects that express at least one of the IRs TIGIT, PD-1, or LAG-3 contained the majority, on average, of CD4+ T cells with inducible HIV genomes, with multi-IR+ CD4+ T cells particularly enriched for integrated HIV DNA [78]; also, TIGIT+ CD4+ T cell frequencies positively correlate with CD4+ T cell HIV DNA content [49], and TIGIT transcription is elevated in cells bearing replication competent latent HIV [79]. Our recent studies indicate that sensing of HIV viral introncontaining RNA by infected macrophages leads to type I interferon secretion and induction of IRs on cocultured T cells [80]. Circulating γδ T cells are known to harbor latent virus at a high frequency [47], therefore it is worth investigating if IR+ γδ T cells, particularly TIGIT+ and multi-IR+ subsets, are selectively harboring inducible HIV genomes.…”

Section: Discussionmentioning

confidence: 85%

Multivariate Computational Analysis of Gamma Delta T cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging

Belkina

Starchenko

Drake

et al. 2018

Preprint

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Even with effective viral control, HIV-infected individuals are at a higher risk for morbidities associated with older age than the general population, and these serious non-AIDS events (SNAEs) track with plasma inflammatory and coagulation markers. The cell subsets driving inflammation in aviremic HIV infection are not yet elucidated. Also, whether ART-suppressed HIV infection causes premature induction of the inflammatory events found in uninfected elderly or if a novel inflammatory network ensues when HIV and older age co-exist is unclear. In this study we measured combinational expression of five inhibitory receptors (IRs) on seven immune cell subsets and 16 plasma markers from peripheral blood mononuclear cells (PBMC) and plasma samples, respectively, from a HIV and Aging cohort comprised of ART-suppressed HIV-infected and uninfected controls stratified by age (≤35 or ≥50 years old). For data analysis, multiple multivariate computational algorithms (cluster identification, characterization, and regression (CITRUS), partial least squares regression (PLSR), and partial least squares-discriminant analysis (PLS-DA)) were used to determine if immune parameter disparities can distinguish the subject groups and to investigate if there is a cross-impact of aviremic HIV and age on immune signatures. IR expression on gamma delta (γδ) T cells exclusively separated HIV+ subjects from controls in CITRUS analyses and secretion of inflammatory cytokines and cytotoxic mediators from γδ T cells tracked with TIGIT expression among HIV+ subjects. Also, plasma markers predicted the percentages of TIGIT+ γδ T cells in subjects with and without HIV in PSLR models, and a PLS-DA model of γδ T cell IR signatures and plasma markers significantly stratified all four of the subject groups (uninfected younger, uninfected older, HIV+ younger, and HIV+ older). These data implicate γδ T cells as an inflammatory driver in ART-suppressed HIV infection and provide evidence of distinct ‘inflamm-aging’ processes with and without ART-suppressed HIV infection.

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“…Upon HIV-1 infection, two strands of genomic single-stranded (ss) RNA are encapsulated in virions. These nucleic acids, as well as HIV-1 transcripts that are generated from proviruses, potentially act as PAMPs [23,24,[32][33][34][35][36][37]. Both RLR family members, including retinoic acid inducible gene I (RIG-I) and melanoma-differentiation-associated protein 5 (MDA5), and TLR family members (TLR7 and TLR8) have been characterized as PRRs of HIV-1 RNAs [27,35].…”

Section: Hiv-1 Rna Sensorsmentioning

confidence: 99%

“…Pathogen-associated molecular patterns (PAMPs) and sensors involved in innate sensing of human immunodeficiency virus type 1 (HIV-1) infection. [36,37] Abortive viral RNA DDX3X MAVS-TRAF3-TBK-IRFs IFNs DCs [29] RIG-I and MDA5, both localized within the cytoplasm, are also reported to activate IFN signaling by detection of both dimeric and monomeric forms of HIV-1 RNA in infected macrophages [23,44]. Stimulation of monocyte-derived macrophages with purified genomic HIV-1 RNA or synthesized HIV-1 ssRNA-derived oligos results in RIG-I-dependent signaling activation.…”

Section: Hiv-1 Rna Sensorsmentioning

confidence: 99%

“…More recently, two elegant studies showed that intron-containing RNA transcribed from the HIV-1 provirus activates innate immune signaling in MDDCs, macrophages, and CD4 + T cells in response to HIV-1 infection. Interestingly, both RIG-I and MDA5, viral sensors that detect cytosolic viral RNAs are not required, whereas the key RLR-adaptor MAVS is essential for signaling transduction [36,37]. Since DDX3X serves as a signaling scaffold to trigger the MAVS-dependent signaling cascade, as described above, it remains to be determined if DDX3X or another uncharacterized RNA sensor upstream of MAVS is responsible for sensing HIV-1 intron-containing RNA for activation of the innate immune response.…”

Section: Infectionmentioning

confidence: 99%

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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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HIV-1 intron-containing RNA expression induces innate immune activation and T cell dysfunction

Cited by 69 publications

References 57 publications

Clinical Characteristics and CT Manifestations of 143 Patients With 2019 Novel Coronavirus Disease (COVID-19) in Taizhou City, Zhejiang, China

Clinical Characteristics and CT Manifestations of 143 Patients With 2019 Novel Coronavirus Disease (COVID-19) in Taizhou City, Zhejiang, China

Multivariate Computational Analysis of Gamma Delta T cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging

Sensor Sensibility—HIV-1 and the Innate Immune Response

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