Multiple Homozygous Variants in the STING-Encoding <i>TMEM173</i> Gene in HIV Long-Term Nonprogressors

Nissen, Sara Konstantin; Pedersen, Jesper; Helleberg, Marie; Kjær, Kathrine; Thavachelvam, Karthiga; Obel, Niels; Tolstrup, Martin; Jakobsen, Martin R.; Mogensen, Trine H.

doi:10.4049/jimmunol.1701284

Cited by 16 publications

(20 citation statements)

References 60 publications

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“…In neither study were differences in R232H prevalence reported. Another study suggests that STING-HAQ homozygosity may result in slower disease progression in HIV-infected individuals (44). Systematic studies using mouse models such as the ones described in this manuscript could be useful in predicting clinical consequences of carrying these genetic variants.…”

Section: Discussionmentioning

confidence: 94%

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

et al. 2020

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Stimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as products of the DNA sensor cGAS (e.g., 2 ′ 3 ′ cGAMP). The two most common alternative allelic variants of STING in humans are STING-R71H-G230A-R293Q (STING-HAQ) and STING-R232H that are found in 20.4% and 13.7-17.6% of the population, respectively. To determine the biologic consequences of these genotypic variations, we generated knock-in mice containing the murine equivalents of each variant and studied their responsiveness to CDNs. Homozygous STING-HAQ (R71H-I229A-R292Q) and STING-R231H mice were found to be unresponsive to all exogenous CDNs tested (ci-di-GMP, ci-di-AMP, 3 ′ 3 ′ cGAMP and Rp,Rp-CDA). Responses of homozygous STING-HAQ mice to endogenous 2 ′ 3 ′ cGAMP was also greatly impaired. However, homozygous STING-R231H mice are fully responsive to 2 ′ 3 ′ cGAMP. Analysis of heterozygous mice revealed reduced responsiveness to exogenous and endogenous CDNs in mice carrying a single copy of STING-HAQ, while STING-R231H heterozygous mice exhibit reduced responsiveness to exogenous but not endogenous CDNs. These findings confirm and extend previous reports by demonstrating differing impact of allelic variation of STING on the ability to sense and respond to exogenous vs. endogenous CDNs. Finally, the STING-R231H variant mouse represents a useful tool with which to examine the relative contributions of STING sensing of exogenous and endogenous CDNs in the context of bacterial infections and CDN-based cancer immunotherapeutics.

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Section: Discussionmentioning

confidence: 94%

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

et al. 2020

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“…Whole-exome sequencing was performed as previously described (Nissen et al, 2018). Variant call files (VCF) were filtered using the approach described in Supplementary Method 1.…”

Section: Methodsmentioning

confidence: 99%

“…Blood was collected in Lithium Heparin-stabilized tubes and isolated as previously described (Nissen et al, 2018). MdMs were differentiated from PBMCs as previously described (Jorgensen et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

Host Genetics, Innate Immune Responses, and Cellular Death Pathways in Poliomyelitis Patients

et al. 2019

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Purpose Poliovirus (PV) is one of the most studied viruses. Despite efforts to understand PV infection within the host, fundamental questions remain unanswered. These include the mechanisms determining the progression to viremia, the pathogenesis of neuronal infection and paralysis in only a minority of patients. Because of the rare disease phenotype of paralytic poliomyelitis (PPM), we hypothesize that a genetic etiology may contribute to the disease course and outcome. Methods We used whole-exome sequencing (WES) to investigate the genetic profile of 18 patients with PPM. Functional analyses were performed on peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MdMs). Results We identified rare variants in host genes involved in interferon signaling, viral replication, apoptosis, and autophagy. Upon PV infection of MdMs, we observed a tendency toward increased viral burden in patients compared to controls, suggesting reduced control of PV infection. In MdMs from patients, the IFNβ response correlated with the viral burden. Conclusion We suggest that genetic variants in innate immune defenses and cell death pathways contribute to the clinical presentation of PV infection. Importantly, this study is the first to uncover the genetic profile in patients with PPM combined with investigations of immune responses and viral burden in primary cells.

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“…All protocols were approved and methods carried out were in accordance with relevant guidelines and regulations. Some of the HIV patients included here have also been described in another study 45 .…”

Section: Methodsmentioning

confidence: 99%

Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules

Nissen

Christiansen

Helleberg

et al. 2018

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Common CCR5-∆32 and HLA alleles only explain a minority of the HIV long-term non-progressor (LTNP) and elite controller (EC) phenotypes. To identify rare genetic variants contributing to the slow disease progression phenotypes, we performed whole exome sequencing (WES) on seven LTNPs and four ECs. HLA and CCR5 allele status, total HIV DNA reservoir size, as well as variant-related functional differences between the ECs, LTNPs, and eleven age- and gender-matched HIV-infected non-controllers on antiretroviral therapy (NCARTs) were investigated. Several rare variants were identified in genes involved in innate immune sensing, CD4-dependent infectivity, HIV trafficking, and HIV transcription mainly within the LTNP group. ECs and LTNPs had a significantly lower HIV reservoir compared to NCARTs. Furthermore, three LTNPs with variants affecting HIV nuclear import showed integrated HIV DNA levels below detection limit after in vitro infection. HIV slow progressors with variants in the TLR and NOD2 pathways showed reduced pro-inflammatory responses compared to matched controls. Low-range plasma levels of fibronectin was observed in a LTNP harboring two FN1 variants. Taken together, this study identified rare variants in LTNPs as well as in one EC, which may contribute to understanding of HIV pathogenesis and these slow progressor phenotypes, especially in individuals without protecting CCR5-∆32 and HLA alleles.

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Multiple Homozygous Variants in the STING-Encoding TMEM173 Gene in HIV Long-Term Nonprogressors

Cited by 16 publications

References 60 publications

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

Selective Loss of Responsiveness to Exogenous but Not Endogenous Cyclic-Dinucleotides in Mice Expressing STING-R231H

Host Genetics, Innate Immune Responses, and Cellular Death Pathways in Poliomyelitis Patients

Whole Exome Sequencing of HIV-1 long-term non-progressors identifies rare variants in genes encoding innate immune sensors and signaling molecules

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