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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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02864900
Contributor : Caroline Passaes <>
Submitted on : Thursday, June 11, 2020 - 1:44:29 PM
Last modification on : Wednesday, October 14, 2020 - 4:07:19 AM

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Pascal Azar, José Mejía, Claire Cénac, Arnoo Shaiykova, Ali Youness, et al.. TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women. JCI Insight, American Society for Clinical Investigation, 2020, 5 (12), pp.e136047. ⟨10.1172/jci.insight.136047⟩. ⟨pasteur-02864900⟩

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