RESUMEN
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.
Asunto(s)
Infecciones por VIH/genética , VIH-1/aislamiento & purificación , Receptor Toll-Like 7/genética , Adulto , Recuento de Linfocito CD4 , Células Cultivadas , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Inmunidad Innata/genética , Masculino , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 7/inmunología , Carga ViralRESUMEN
BACKGROUND: Homozygosity (Delta32/Delta32) for the 32 bp deletion in the chemokine receptor 5 (CCR5) gene is associated with strong resistance against HIV infection. Heterozygosity is associated with protection of HIV-1 disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped a population of 737 HIV-positive adults and 463 healthy controls for the CCR5Delta32 deletion and found heterozygous frequencies of 16.2% (HIV-negative) and 17.5% (HIV-positive) among Caucasian individuals. Analysis of CCR5Delta32 influence on disease progression showed notably lower viral setpoints and a longer time to a CD4 count of <200 microl(-1) in seroconverters heterozygous for the deletion. Furthermore, we identified one HIV-positive man homozygous for the Delta32 deletion. CONCLUSIONS/SIGNIFICANCE: The protective effect of CCR5 Delta32 heterozygosity is confirmed in a large cohort of German seroconverters. The HIV-infected CCR5 Delta32 homozygous individual, however, displays extremely rapid disease progression. This is the 12th case of HIV-infection in this genotype described worldwide.
Asunto(s)
Infecciones por VIH/genética , Seropositividad para VIH/genética , VIH-1/metabolismo , Mutación , Receptores CCR5/genética , Receptores CCR5/fisiología , Adulto , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Genotipo , Alemania , Infecciones por VIH/sangre , Heterocigoto , Homocigoto , Humanos , MasculinoRESUMEN
Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinositol anchor induces signaling in host cells via TLR-2 and -4, whereas hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of proinflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response in malaria, including cytokine induction and fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a rare previously undescribed mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9 Toll/IL-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls and was even more frequent in severe malaria patients (24.1%, P < 0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (P = 0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred 1.5- and 2.6-fold increased risks of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation.
Asunto(s)
Predisposición Genética a la Enfermedad , Malaria Falciparum/genética , Polimorfismo Genético , Receptor Toll-Like 4/genética , Secuencia de Bases , Línea Celular , Niño , Preescolar , Cartilla de ADN , Femenino , Ghana/epidemiología , Humanos , Lactante , Malaria Falciparum/epidemiología , Masculino , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mutación Missense/genética , Oportunidad Relativa , Prevalencia , Análisis de Secuencia de ADN , Transducción de Señal/genética , Receptor Toll-Like 2/genética , Receptor Toll-Like 9/genéticaRESUMEN
Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinisitol anchor induces signaling in host cells via TLR-2 and -4, while hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of pro-inflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response, including pro-inflammatory cytokine induction and malarial fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a new, rare mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9/interleukin-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls, and was even more frequent in severe malaria patients (24.1%, p<0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (p=0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred an 1.5- and 2.6-fold increased risk of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation. However some gray areas also suggest the scope for further improvements.