TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women
Pascal Azar, José Enrique Mejía, Claire Cenac, Arnoo Shaiykova, Ali Youness, Sophie Laffont, Asma Essat, Jacques Izopet, Caroline Passaes, Michaela Müller-Trutwin, Pierre Delobel, Laurence Meyer, Jean-Charles Guéry
Pascal Azar, José Enrique Mejía, Claire Cenac, Arnoo Shaiykova, Ali Youness, Sophie Laffont, Asma Essat, Jacques Izopet, Caroline Passaes, Michaela Müller-Trutwin, Pierre Delobel, Laurence Meyer, Jean-Charles Guéry
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Research Article AIDS/HIV Immunology

TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women

Abstract

Type I IFN (IFN-I) production by plasmacytoid DCs (pDCs) occurs during acute HIV-1 infection in response to TLR7 stimulation, but the role of pDC-derived IFN-I in controlling or promoting HIV-1 infection is ambiguous. We report here a sex-biased interferogenic phenotype for a frequent single-nucleotide polymorphism of human TLR7, rs179008, displaying an impact on key parameters of acute HIV-1 infection. We show allele rs179008 T to determine lower TLR7 protein abundance in cells from women, specifically — likely by diminishing TLR7 mRNA translation efficiency through codon usage. The hypomorphic TLR7 phenotype is mirrored by decreased TLR7-driven IFN-I production by female pDCs. Among women from the French ANRS PRIMO cohort of acute HIV-1 patients, carriage of allele rs179008 T associated with lower viremia, cell-associated HIV-1 DNA, and CXCL10 (IP-10) plasma concentrations. RNA viral load was decreased by 0.85 log10 (95% CI, −1.51 to −0.18) among T/T homozygotes, who also exhibited a lower frequency of acute symptoms. TLR7 emerges as an important control locus for acute HIV-1 viremia, and the clinical phenotype for allele rs179008 T, carried by 30%–50% of European women, supports a beneficial effect of toning down TLR7-driven IFN-I production by pDCs during acute HIV-1 infection.

Authors

Pascal Azar, José Enrique Mejía, Claire Cenac, Arnoo Shaiykova, Ali Youness, Sophie Laffont, Asma Essat, Jacques Izopet, Caroline Passaes, Michaela Müller-Trutwin, Pierre Delobel, Laurence Meyer, Jean-Charles Guéry

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Figure 1

Sex-specific effect of the rs179008 T allele on the IFN-α expression phenotype.

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Sex-specific effect of the rs179008 T allele on the IFN-α expression phe...
(A–F) Quantitation of IFN-α in culture supernatants of male (A–C) and female (D–F) PBMCs stimulated ex vivo with TLR7 ligands as shown, sampled 6, 12, and 24 hours after stimulation or 24 hours for nonstimulated (Unstim.) control cells. ELISA IFN-α values (pg/mL) were normalized to flow-cytometrically determined pDC numbers for each donor; see Supplemental Figure 2A for the Lin−CD123+BDCA4+ gating strategy. Each dot represents 1 donor; horizontal bars indicate mean values ± SEM. The number of donors by genotype is indicated in the plot legend. Groups were compared by a 2-way ANOVA followed by Sidak’s multiple comparisons test. N.D., not detectable (i.e., below the 30 pg/mL detection threshold of the assay). (G–I) Frequency of IFN-α–producing pDCs. Freshly isolated male and female PBMCs were stimulated with 0.3 μg/mL R-848 (G), HIV-1–derived GagRNA1166 (H), or 1 μg/mL R-837 (I). The frequency of IFN-α–producing pDCs was determined by flow cytometry, as above. Each dot represents 1 donor; horizontal bars indicate mean values ± SD. Groups were compared by the Kruskal-Wallis test corrected for multiple comparisons by controlling the FDR (Benjamini-Hochberg method). Data for a small number of T/T female donors studied in parallel are plotted (in red) but were not included in the statistical tests.