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

• DOI: 10.1172/jci.insight.136047
• Publication Date: 2020-06-17T15:01:33Z
• Authors: Pascal Azar; José Enrique Mejía; Claire Cenac; Arnoo Shaiykova; Ali Youness; Sophie Laffont; Asma Essat; Jacques Izopet; Caroline Passaes; Michaela Müller-T...; Pierre Delobel; Laurence Meyer; Jean-Charles Guéry
• Keywords: Adult; CD4-Positive T-Lymphocytes; 0301 basic medicine; [SDV.IMM] Life Sciences [q-bio]/Immunology; Interferon-alpha; HIV Infections; Dendritic Cells; Middle Aged; 3. Good health; 03 medical and health sciences; Toll-Like Receptor 7; 616; HIV-1; [SDV.IMM]Life Sciences [q-bio]/Immunology; Humans; Female; Viremia

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.