A functional toll-like receptor 8 variant is associated with HIV disease restriction.
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.


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-kappaB 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.
Oh
D-Y
DY
Institute of Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Taube
S
S
Hamouda
O
O
Kücherer
C
C
Poggensee
G
G
Jessen
H
H
Eckert
J K
JK
Neumann
K
K
Storek
A
A
Pouliot
M
M
Borgeat
P
P
Oh
N
N
Schreier
E
E
Pruss
A
A
Hattermann
K
K
Schumann
R R
RR
D000328:Adult; D002460:Cell Line; D018450:Disease Progression; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051200:Toll-Like Receptor 8 / Q000235:genetics*
D016328:NF-kappa B; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8