Objectives: Toll-like receptors (TLRs) play an important role in the innate immune response to pathogens. TLR7 recognizes RNA of various viruses including HIV. The objective of this study was to examine the influence of individual genetic variations of TLR7 on the susceptibility to and progression of HIV disease.
Method: We genotyped a population of 734 HIV-positive adults and 545 healthy controls for three TLR7 single nucleotide polymorphisms. The frequency of TLR7 genetic variations was assessed and related to HIV disease progression. Furthermore, we analyzed peripheral blood mononuclear cells obtained from healthy individuals differing in their TLR7 genotype and assessed their response to a TLR7-specific ligand ex vivo.
Results: Presence of the most frequent TLR7 polymorphism, TLR7 Gln11Leu, was associated with higher viral loads and accelerated progression to advanced immune suppression in HIV patients. Furthermore, in women this polymorphism may be associated with increased HIV-1 susceptibility as it was found more frequently among patients as compared with controls. Peripheral blood mononuclear cells from polymorphism carriers secreted significantly less IFN-α following TLR7 activation, whereas IL-6 production remained unaltered.
Conclusion: This is the first report of a functional TLR7 variant to be associated with susceptibility to and a more severe clinical course of HIV-1 disease. These results may have implications for the risk assessment of individual patients as well as for HIV-1 therapy and vaccination strategies in the future.
aInstitute for Microbiology and Hygiene, Charité University Medical Center, Germany
bRobert Koch Institute, Germany
cDepartment of Medical Biometry and Clinical Epidemiology, Charité University Medical Center, Germany
dThe Berlin Trial on HIV and TLR SNPs, Gemeinschaftspraxis Jessen-Jessen-Stein, Germany
eInstitute of Transfusion Medicine, Charité University Medical Center, Berlin, Germany.
* Present address: The Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts, USA.
Received 22 August, 2008
Revised 8 October, 2008
Accepted 14 October, 2008
Correspondence to Ralf R. Schumann, MD, PhD, Institute for Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, Dorotheenstr. 96, 10117 Berlin, Germany. Tel: +49 30 450 524141; fax: +49 30 450 524941; e-mail: firstname.lastname@example.org