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

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

doi:10.1172/jci.insight.136047

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.

Highlights

The intracellular TLRs — TLR3, TLR7, TLR8, and TLR9 — recognize autologous and microbial nucleic acids and are critical components of innate antiviral immunity [1]
Recent findings strongly suggest a detrimental effect of plasmacytoid DCs (pDCs) and IFN-I during the chronic phase of HIV-1 infection, the early-stage role of IFN-I produced by pDCs as a result of TLR7 activation is still not fully understood [41]
We have addressed this issue firstly through the functional characterization of a frequent TLR7 Single-nucleotide polymorphisms (SNPs), rs179008, which we found to exert a quantitative effect on TLR7 protein synthesis and pDC IFN-I production in women and secondly by analyzing the association of TLR7 polymorphisms with clinical parameters of HIV-1 infection

Summary

Introduction

The intracellular TLRs — TLR3, TLR7, TLR8, and TLR9 — recognize autologous and microbial nucleic acids and are critical components of innate antiviral immunity [1]. Studies of macaques infected with SIV to model the pathogenesis of human AIDS identified pDCs as the critical source of IFN-I in vivo [7,8,9,10]. In line with the macaque model, depleting the pDCs of humanized mice prior to HIV-1 infection boosted viral replication and abolished serum IFN-I elevation and the expression of IFN-stimulated genes [12]. These investigations are supportive of a beneficial role for IFN-I during early-stage HIV-1 infection, opposing the spread of the virus and its expansion within lymph nodes.

Methods

Results

Conclusion