Abstract
In HIV infection, TLR7-triggered IFN-α production exerts a direct antiviral effect through the inhibition of viral replication, but may also be involved in immune pathogenesis leading to AIDS. TLR7 could also be an important mediator of vaccine efficacy. In this study, we analyzed polymorphisms in the X-linked TLR7 gene in the rhesus macaque model of AIDS. Upon resequencing of the TLR7 gene in 36 rhesus macaques of Indian origin, 12 polymorphic sites were detected. Next, we identified three tightly linked single nucleotide polymorphisms (SNP) as being associated with survival time. Genotyping of 119 untreated, simian immunodeficiency virus (SIV)-infected male rhesus macaques, including an ‘MHC adjusted’ subset, revealed that the three TLR7 SNPs are also significantly associated with set-point viral load. Surprisingly, this effect was not observed in 72 immunized SIV-infected male monkeys. We hypothesize (i) that SNP c.13G>A in the leader peptide is causative for the observed genotype-phenotype association and that (ii) the underlying mechanism is related to RNA secondary structure formation. Therefore, we investigated a fourth SNP (c.-17C>T), located 17 bp upstream of the ATG translation initiation codon, that is also potentially capable of influencing RNA structure. In c.13A carriers, neither set-point viral load nor survival time were related to the c.-17C>T genotype. In c.13G carriers, by contrast, the c.-17C allele was significantly associated with prolonged survival. Again, no such association was detected among immunized SIV-infected macaques. Our results highlight the dual role of TLR7 in immunodeficiency virus infection and vaccination and imply that it may be important to control human AIDS vaccine trials, not only for MHC genotype, but also for TLR7 genotype.
Highlights
Toll-like receptor 7 (TLR7) localizes to intracellular vesicles in antigen-presenting cells such as plasmacytoid dendritic cells, macrophages, memory B cells and T cells
Variability of the rhesus TLR7 gene Like in humans and many other species, the X-linked TLR7 gene in rhesus macaque contains three exons, namely two untranslated exons encompassing the 59 untranslated region (59UTR) and the ATG translation initiation codon, and exon 3 spanning the sequence coding for the leader peptide, the mature TLR7 polypeptide and a 39 untranslated region (39UTR) of about 1700 bp not yet annotated firmly in rhesus macaque
We had to establish a panel of polymorphisms first before we could assess the impact of TLR7 gene variability upon the progression and outcome of simian immunodeficiency virus (SIV) infection in this species
Summary
Toll-like receptor 7 (TLR7) localizes to intracellular vesicles in antigen-presenting cells such as plasmacytoid dendritic cells, macrophages, memory B cells and T cells. In these cells, TLR7 functions as a receptor for pathogen recognition in that it binds ligands like uridine-rich single-stranded (ss) RNAs or certain small interfering RNAs [1,2,3,4]. Targeting of TLR7 by synthetic agonists like polyUs21, or conjugation of TLR7 to a protein vaccine, can prime highfrequency polyfunctional type 1 T helper cell (Th1) and cytotoxic T-lymphocyte (CTL) response, probably through the activation of plasmacytoid dendritic cells (PDC) [11,12,13].
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