A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression

Oh, Djin-Ye; Baumann, Konstantin; Hamouda, Osamah; Eckert, Jana; Neumann, Konrad; Kücherer, Claudia; Bartmeyer, Barbara; Poggensee, Gabriele; Oh, Nari; Pruß, Axel; Jessen, Heiko; Schumann, Ralf R.

doi:10.1097/qad.0b013e32831fb540

Cited by 98 publications

(96 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These are the only reported effects of the SNP at the protein/cellular level and these data were mostly (for livers), or completely (for pDCs), derived from hemizygous males. As stated above, however, most reported clinical effects of the SNP are observed in females (Oh et al, 2009;Schott et al, 2007b). We also identified effects of the SNP only in females.…”

Section: Discussionmentioning

confidence: 66%

“…In both infections, the variant allele associated with higher disease prevalence and augmented disease progression, and with reduced response to IFNα-therapy for HCV (Oh et al, 2009;Said et al, 2014;Askar et al, 2010;Schott et al, 2007b;Fakhir et al, 2018). In all these studies, effects were most prominent in (mostly rs179008 heterozygous) females and all studies predominantly contained Caucasian individuals.…”

Section: Discussionmentioning

confidence: 98%

“…PBMCs from males carrying the variant T allele secreted less IFNα upon TLR7 ligation than those from males with the more common A (i.e. WT) allele (Oh et al, 2009). Furthermore, in HIV, the variant allele associated with higher infection rates, viral load and disease progression (Oh et al, 2009;Said et al, 2014).…”

Section: Introductionmentioning

confidence: 97%

“…WT) allele (Oh et al, 2009). Furthermore, in HIV, the variant allele associated with higher infection rates, viral load and disease progression (Oh et al, 2009;Said et al, 2014). In HCV, the variant was more prevalent among chronic patients as compared to healthy controls and related to a poor IFNα treatment response (Schott et al, 2007a;Askar et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

View full text Add to dashboard Cite

A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

show abstract

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A loss-offunction TLR7 polymorphism is correlated with elevated viral loads and a more rapid progression to disease (42). Studies have also shown that a more potent IL-10 response during acute HIV-1 infection is correlated with lower set points and reduced pathogenesis (43,44).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 7 Inhibits Early Acute Retroviral Infection through Rapid Lymphocyte Responses

Browne

2013

J Virol

View full text Add to dashboard Cite

Early events during retroviral infection play a critical role in determining the course of infection and pathogenesis, but the mechanisms that regulate this phase of infection are poorly understood. Toll-like receptor 7 (TLR7) is required for promoting germinal center reactions and virus-specific neutralizing antibodies at later time points postinfection, but TLR7's role in early acute infection has not been determined. By infecting TLR7-deficient mice with a retroviral pathogen, Friend virus (FV), I determined that TLR7 potently inhibits retroviral replication during the first 5 days of infection and is required for rapid secretion of virus-specific IgM and interleukin-10 (IL-10) in response to infection. Although the IgM response was nonneutralizing, plasmas from wild-type mice but not TLR7-deficient mice inhibited FV replication when passively transferred to infected mice, suggesting an indirect mechanism of antibody function. Interestingly, IL-10 was secreted primarily by CD4 T cells, and IL-10-deficient mice also exhibited accelerated early virus spread, demonstrating that this response inhibits acute infection. Surprisingly, TLR7-deficient mice exhibited normal or elevated secretion of proinflammatory cytokines during acute infection, revealing the existence of a TLR7-independent retrovirus-sensing pathway that drives inflammatory cytokine secretion. Together, these results establish a previously unappreciated role for lymphocytes in mediating rapid TLR7-dependent inhibition of early retroviral infection through nonneutralizing IgM and IL-10.

show abstract

Presence of Genetic Variants Among Young Men With Severe COVID-19

Made

Simons

Schuurs-Hoeijmakers

et al. 2020

JAMA

680

623

View full text Add to dashboard Cite

IMPORTANCESevere coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).OBJECTIVE To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSCase series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.EXPOSURE Severe COVID-19. MAIN OUTCOME AND MEASURESResults of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. RESULTSThe 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c. 2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. CONCLUSIONS AND RELEVANCEIn this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

show abstract

A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression

Cited by 98 publications

References 66 publications

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

Toll-Like Receptor 7 Inhibits Early Acute Retroviral Infection through Rapid Lymphocyte Responses

Presence of Genetic Variants Among Young Men With Severe COVID-19

Contact Info

Product

Resources

About