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-alpha 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.
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, TLR7Gln11Leu, 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-alpha 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.
Authors: Romel D Mackelprang; Abigail W Bigham; Connie Celum; Guy de Bruyn; Kristin Beima-Sofie; Grace John-Stewart; Allan Ronald; Nelly R Mugo; Kati J Buckingham; Michael J Bamshad; James I Mullins; M Juliana McElrath; Jairam R Lingappa Journal: J Infect Dis Date: 2013-12-10 Impact factor: 5.226
Authors: Rachel Lubong Sabado; Anna Pavlick; Sacha Gnjatic; Crystal M Cruz; Isabelita Vengco; Farah Hasan; Meredith Spadaccia; Farbod Darvishian; Luis Chiriboga; Rose Marie Holman; Juliet Escalon; Caroline Muren; Crystal Escano; Ethel Yepes; Dunbar Sharpe; John P Vasilakos; Linda Rolnitzsky; Judith Goldberg; John Mandeli; Sylvia Adams; Achim Jungbluth; Linda Pan; Ralph Venhaus; Patrick A Ott; Nina Bhardwaj Journal: Cancer Immunol Res Date: 2015-01-29 Impact factor: 11.151
Authors: Nicholas W Lukacs; Joost J Smit; Sumanta Mukherjee; Susan B Morris; Gabriel Nunez; Dennis M Lindell Journal: J Immunol Date: 2010-07-12 Impact factor: 5.422