Type I IFN-mediated sex differences in immune response to HIV-1


In acute HIV-1 infection, women control viral replication better than men. In contrast, women develop increased immune activation and faster loss of CD4+ T cells during untreated chronic HIV-1 infection. Increasing data indicate that these sex differences in the manifestation of HIV-1 disease are mediated by sex-specific differences in antiviral immunity. In previous studies we demonstrated that pDCs derived from women produce more IFNα in response to HIV-1 than pDCs from men, potentially contributing to the better control of viremia in acute infection. This increased IFNα production in response to HIV-1 however also led to significantly higher immune activation and faster loss of CD4+ T cells in chronically HIV-1-infected women. Taken together these data strongly suggest that sex differences in Type I IFN production result in differences in HIV-1 disease manifestations between women and men. However, the precise molecular mechanisms underlying these sex differences in HIV-1 and other infectious diseases remain poorly understood. We hypothesize that X chromosome-encoded genes play a critical role in regulating Type I IFN responses, and that gene-dose effects resulting from escape from X chromosome inactivation (XCI) contribute to sex-specific differences in antiviral immunity, using HIV-1 as a model. We will furthermore test the hypothesis that changes in levels of sex hormones can regulate Type I IFN responses of pDCs, using longitudinal samples from a human transgender cohort. Taken together, these studies will identify critical mechanisms underlying sex-specific differences in antiviral immunity, and provide rationale for the design of interventions that take these differences between women and men into account.

PROJECT-RELATED PUBLICATIONS


Hagen SH, Hennesen J, Altfeld M. (2021)
Assessment of escape from X chromosome inactivation and gene expression in single human immune cells
STAR Protoc 2:100641

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Sven Hendrik Hagen, Florian Henseling, Jana Hennesen, Hélène Savel, Solenne Delahaye, Laura Richert, Susanne Maria Ziegler, Marcus Altfeld. (2020)
Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level
Cell Rep 33:108485

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Adland E, Millar J, Bengu N, Muenchhoff M, Fillis R, Sprenger K, Ntlantsana V, Roider J, Vieira V, Govender K, Adamson J, Nxele N, Ochsenbauer C, Kappes J, Mori L, van Lobenstein J, Graza Y, Chinniah K, Kapongo C, Bhoola R, Krishna M, Matthews PC, Poderos RP, Lluch MC, Puertas MC, Prado JG, McKerrow N, Archary M, Ndung'u T, Groll A, Jooste P, Martinez-Picado J, Altfeld M, Goulder P. (2020)
Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection
Nat Commun 11:1767

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Lotter H, Altfeld M (2019)
Sex differences in immunity
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Scully EP, Gandhi M, Johnston R, Hoh R, Lockhart A, Dobrowolski C, Pagliuzza A, Milush JM, Baker CA, Girling V, Ellefson A, Gorelick R, Lifson J, Altfeld M, Alter G, Cedars M, Solomon A, Lewin SR, Karn J, Chomont N, Bacchetti P, Deeks SG. (2019)
Sex-Based Differences in Human Immunodeficiency Virus Type 1 Reservoir Activity and Residual Immune Activation
J Infect Dis. 219:1084-1094

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Rechtien A, Altfeld M. (2019)
Sexual dimorphism in HIV-1 infection
Semin Immunopathol 41:195-202

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Ziegler SM, Beisel C, Sutter K, Griesbeck M, Hildebrandt H, Hagen SH, Dittmer U, Altfeld M. (2017)
Human pDCs display sex-specific differences in type I interferon subtypes and interferon α/β receptor expression
Eur J Immunol 47:251-256

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Griesbeck M, Ziegler S, Laffont S, Smith N, Chauveau L, Tomezsko P, Sharei A, Kourjian G, Porichis F, Hart M, Palmer CD, Sirignano M, Beisel C, Hildebrandt H, Cénac C, Villani AC, Diefenbach TJ, Le Gall S, Schwartz O, Herbeuval JP, Autran B, Guéry JC, Chang JJ, Altfeld M. (2015)
Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women
J Immunol. 195:5327-36

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Addo MM, Altfeld M. (2014)
Sex-based differences in HIV type 1 pathogenesis
J Infect Dis. 209 Suppl 3:S86-92

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Chang JJ, Woods M, Lindsay RJ, Doyle EH, Griesbeck M, Chan ES, Robbins GK, Bosch RJ, Altfeld M. (2013)
Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication
J Infect Dis 208:830-8

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Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, Wen TF, Lindsay RJ, Orellana L, Mildvan D, Bazner S, Streeck H, Alter G, Lifson JD, Carrington M, Bosch RJ, Robbins GK, Altfeld M. (2009)
Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1
Nat Med 15: 955-9

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