Abstract
Background. Toll-like receptors (TLRs) play an important role in the innate immune response to pathogens. TLR8 has been found to recognize RNA derived from various viruses, including human immunodeficiency virus (HIV). Presently, very little is known about the influence of TLR8 genetic variation on susceptibility to and progression of HIV disease. Methods and results. We genotyped a population of 782 HIV-positive adults and 550 healthy control subjects for 3 nonsynonymous TLR8 single-nucleotide polymorphisms. We found that the presence of the most frequent TLR8 polymorphism, TLR8 A1G (rs3764880), confers a significantly protective effect regarding progression of the disease. In overexpression assays, we demonstrated that this receptor variant displays impaired NF-κB activation in vitro. Furthermore, we analyzed different cell types obtained from individuals differing in their TLR8 genotype and assessed their response to TLR8 ligands in vitro. The presence of the mutated receptor variant was associated with modulation of cytokine secretion profiles and lipid mediator synthesis patterns in monocytes and neutrophils. Conclusions. This first report of a functional TLR8 variant associated with a different clinical course of an RNA viral disease may have implications for the individual risk assessment of patients infected with HIV and other RNA viruses as well as for future HIV vaccine development.
| Originalsprache | Englisch |
|---|---|
| Zeitschrift | Journal of Infectious Diseases |
| Jahrgang | 198 |
| Ausgabenummer | 5 |
| Seiten (von - bis) | 701-709 |
| Seitenumfang | 9 |
| ISSN | 0022-1899 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - 01.09.2008 |
Fördermittel
Received 29 November 2007; accepted 8 March 2008; electronically published 7 July 2008. Potential conflicts of interest: none reported. Financial support: Charité-Universitätsmedizin Berlin (Rahel Hirsch Grant to D.-Y.O.); Deutsche Forschungsgemeinschaft (grants to R.R.S.). Participating collaborators are listed after the text. a D.-Y.O. and S.T. contributed equally to this work. b Present affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan. Reprints or correspondence: Dr. Ralf R. Schumann, Institute of Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, Dorotheenstr. 96, 10117 Berlin, Germany ([email protected]). We gratefully acknowledge the patients, their families, and the clinicians whose participation in the German HIV-1 Seroconverter Study and the Berlin Trial on HIV and TLR SNPs made these investigations possible. We are grateful to Fränzi Creutzburg and Diana Woellner (Charité; Berlin) for excellent technical assistance, and we thank Sabrina Neumann and Hanno von Spreckelsen for skillfull technical assistance in the preparation and asserva-tion of DNA samples from seroconverters (German HIV-1 Seroconverter Study). Tib Molbiol/GenExpress (Berlin, Germany) is thanked for probe design and excellent genotyping support, and Martin Meixner of Cyano Biotech is thanked for outstanding help with sequence analysis. Carsten J. Kirschning (Munich, Germany) kindly supplied the TLR8 isoform B expression vector. Carmen Zedlack (Praxisgemeinschaft Jessen; Berlin), Christian Kollan, and Parvin Ghassim (Robert Koch-Institut; Berlin) provided invaluable data-management support.
Strategische Forschungsbereiche und Zentren
- Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)
UN SDGs
Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung
