TLR7 Dosage Polymorphism Shapes Interferogenesis and HIV-1 Acute Viremia in Women

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2020 Jun 20

PMID 32554924

Citations 27

Authors

Pascal Azar

Jose Enrique Mejia

Claire Cenac

Arnoo Shaiykova

Ali Youness

Sophie Laffont

Asma Essat

Jacques Izopet

Caroline Passaes

Michaela Muller-Trutwin

Pierre Delobel

Laurence Meyer

Jean-Charles Guery

Affiliations

Soon will be listed here.

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.

Citing Articles

Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis.

Du Y, Faz-Lopez B, Ah Kioon M, Cenac C, Pierides M, Lakin K J Exp Med. 2024; 222(3).

PMID: 39670995 PMC: 11639950. DOI: 10.1084/jem.20231809.

rs179008 (A/T) and rs3853839 (C/G) polymorphisms are associated with variations in IFN-α levels in HTLV-1 infection.

Santana E, Dos Santos Ferreira F, Dos Santos Brito W, Lopes F, de Lima A, Neto G Front Immunol. 2024; 15:1462352.

PMID: 39650644 PMC: 11621001. DOI: 10.3389/fimmu.2024.1462352.

The impact of sex on HIV immunopathogenesis and therapeutic interventions.

Mihealsick E, Word A, Scully E J Clin Invest. 2024; 134(18).

PMID: 39286972 PMC: 11405047. DOI: 10.1172/JCI180075.

Decreased TLR7 expression was associated with airway eosinophilic inflammation and lung function in asthma: evidence from machine learning approaches and experimental validation.

Yan K, Liang Y Eur J Med Res. 2024; 29(1):116.

PMID: 38341589 PMC: 10858610. DOI: 10.1186/s40001-023-01622-5.

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size.

Dwivedi A, Gornalusse G, Siegel D, Barbehenn A, Thanh C, Hoh R PLoS Pathog. 2023; 19(11):e1011114.

PMID: 38019897 PMC: 10712869. DOI: 10.1371/journal.ppat.1011114.

References

Telenti A . HIV: The mixed blessing of interferon. Nature. 2014; 511(7511):537-8. DOI: 10.1038/nature13517. View

Oh D, Baumann K, Hamouda O, Eckert J, Neumann K, Kucherer C . A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression. AIDS. 2008; 23(3):297-307. DOI: 10.1097/QAD.0b013e32831fb540. View

Philbin V, Iqbal M, Boyd Y, Goodchild M, Beal R, Bumstead N . Identification and characterization of a functional, alternatively spliced Toll-like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens. Immunology. 2005; 114(4):507-21. PMC: 1782111. DOI: 10.1111/j.1365-2567.2005.02125.x. View

Barreiro L, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell J . Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet. 2009; 5(7):e1000562. PMC: 2702086. DOI: 10.1371/journal.pgen.1000562. View

Myasnikov A, Afonina Z, Menetret J, Shirokov V, Spirin A, Klaholz B . The molecular structure of the left-handed supra-molecular helix of eukaryotic polyribosomes. Nat Commun. 2014; 5:5294. DOI: 10.1038/ncomms6294. View

von Sydow M, Sonnerborg A, Gaines H, Strannegard O . Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. AIDS Res Hum Retroviruses. 1991; 7(4):375-80. DOI: 10.1089/aid.1991.7.375. View

Herbeuval J, Nilsson J, Boasso A, Hardy A, Kruhlak M, Anderson S . Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proc Natl Acad Sci U S A. 2006; 103(18):7000-5. PMC: 1444883. DOI: 10.1073/pnas.0600363103. View

Pastrana D, Buck C, Pang Y, Thompson C, Castle P, FitzGerald P . Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papillomavirus neutralization assay for HPV16 and HPV18. Virology. 2004; 321(2):205-16. DOI: 10.1016/j.virol.2003.12.027. View

Dominguez-Villar M, Gautron A, de Marcken M, Keller M, Hafler D . TLR7 induces anergy in human CD4(+) T cells. Nat Immunol. 2014; 16(1):118-28. PMC: 4413902. DOI: 10.1038/ni.3036. View

10.

Novoa E, Pavon-Eternod M, Pan T, Ribas de Pouplana L . A role for tRNA modifications in genome structure and codon usage. Cell. 2012; 149(1):202-13. DOI: 10.1016/j.cell.2012.01.050. View

11.

Seillet C, Laffont S, Tremollieres F, Rouquie N, Ribot C, Arnal J . The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling. Blood. 2011; 119(2):454-64. DOI: 10.1182/blood-2011-08-371831. View

12.

Bruel T, Dupuy S, Demoulins T, Rogez-Kreuz C, Dutrieux J, Corneau A . Plasmacytoid dendritic cell dynamics tune interferon-alfa production in SIV-infected cynomolgus macaques. PLoS Pathog. 2014; 10(1):e1003915. PMC: 3907389. DOI: 10.1371/journal.ppat.1003915. View

13.

Barrat F, Su L . A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection. J Exp Med. 2019; 216(9):1974-1985. PMC: 6719431. DOI: 10.1084/jem.20181359. View

14.

Nakamura Y, Gojobori T, Ikemura T . Codon usage tabulated from international DNA sequence databases: status for the year 2000. Nucleic Acids Res. 1999; 28(1):292. PMC: 102460. DOI: 10.1093/nar/28.1.292. View

15.

Ploquin M, Madec Y, Casrouge A, Huot N, Passaes C, Lecuroux C . Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset. PLoS Pathog. 2016; 12(8):e1005774. PMC: 4980058. DOI: 10.1371/journal.ppat.1005774. View

16.

Jacquelin B, Mayau V, Targat B, Liovat A, Kunkel D, Petitjean G . Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest. 2009; 119(12):3544-55. PMC: 2786805. DOI: 10.1172/JCI40093. View

17.

Teijaro J, Ng C, Lee A, Sullivan B, Sheehan K, Welch M . Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science. 2013; 340(6129):207-11. PMC: 3640797. DOI: 10.1126/science.1235214. View

18.

Griesbeck M, Ziegler S, Laffont S, Smith N, Chauveau L, Tomezsko P . Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women. J Immunol. 2015; 195(11):5327-36. PMC: 4654231. DOI: 10.4049/jimmunol.1501684. View

19.

Deng Y, Zhao J, Sakurai D, Kaufman K, Edberg J, Kimberly R . MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet. 2013; 9(2):e1003336. PMC: 3585142. DOI: 10.1371/journal.pgen.1003336. View

20.

Souyris M, Cenac C, Azar P, Daviaud D, Canivet A, Grunenwald S . escapes X chromosome inactivation in immune cells. Sci Immunol. 2018; 3(19). DOI: 10.1126/sciimmunol.aap8855. View