TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women.
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.
['Azar|Pascal|P|', 'Mejía|José Enrique|JE|', 'Cenac|Claire|C|', 'Shaiykova|Arnoo|A|', 'Youness|Ali|A|', 'Laffont|Sophie|S|', 'Essat|Asma|A|', 'Izopet|Jacques|J|', 'Passaes|Caroline|C|', 'Müller-Trutwin|Michaela|M|', 'Delobel|Pierre|P|', 'Meyer|Laurence|L|', 'Guéry|Jean-Charles|JC|']
D000328:Adult D015496:CD4-Positive T-Lymphocytes D003713:Dendritic Cells D005260:Female D015658:HIV Infections D015497:HIV-1 D006801:Humans D016898:Interferon-alpha D008875:Middle Aged D051199:Toll-Like Receptor 7 D014766:Viremia
AIDS/HIV Immunology Innate immunity