Advances in HIV Research Using Mass Cytometry

Ornatsky O, Bandura D, Baranov V, Nitz M, Winnik MA, Tanner S. Highly multiparametric analysis by mass cytometry. J Immunol Methods. 2010;361(1–2):1–20. https://doi.org/10.1016/j.jim.2010.07.002.

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Bendall SC, Simonds EF, Qiu P, el Amir AD, Krutzik PO, Finck R, et al. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science. 2011;332(6030):687–96. https://doi.org/10.1126/science.1198704.

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George AF, Luo X, Neidleman J, Hoh R, Vohra P, Thomas R, et al. Deep phenotypic analysis of blood and lymphoid T and NK cells from HIV+ controllers and ART-suppressed individuals. Front Immunol. 2022;13:803417. https://doi.org/10.3389/fimmu.2022.803417.

•• Ma T, McGregor M, Giron L, Xie G, George AF, Abdel-Mohsen M, et al. Single-cell glycomics analysis by CyTOF-Lec reveals glycan features defining cells differentially susceptible to HIV. Elife. 2022;11. https://doi.org/10.7554/eLife.78870. This study developed the technique CyTOF-Lec, which simultaneously profiles both cell-surface antigens and glycans.

• Ma T, Luo X, George AF, Mukherjee G, Sen N, Spitzer TL, et al. HIV efficiently infects T cells from the endometrium and remodels them to promote systemic viral spread. Elife. 2020;9:e55487. https://doi.org/10.7554/eLife.55487. This study used CyTOF and PP-SLIDE to determine how HIV infects and remodels cells of the endometrium.

•• Neidleman J, Luo X, Frouard J, Xie G, Hsiao F, Ma T, et al. Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir. Elife. 2020;9:e55487. https://doi.org/10.7554/eLife.60933. This study used PP-SLIDE to chart the in vivo inducible HIV reservoir.

Xie G, Moron-Lopez S, Siegel DA, Yin K, Polos A, Cohen J, et al. Common and divergent features of T cells from blood, gut, and genital tract of antiretroviral therapy-treated HIV(+) women. J Immunol. 2022;208(7):1790–801. https://doi.org/10.4049/jimmunol.2101102.

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•• Cavrois M, Banerjee T, Mukherjee G, Raman N, Hussien R, Rodriguez BA, et al. Mass cytometric analysis of HIV entry, replication, and remodeling in tissue CD4+ T cells. Cell Rep. 2017;20(4):984–98. https://doi.org/10.1016/j.celrep.2017.06.087. This study originally developed the method PP-SLIDE, which leverages high-dimensional CyTOF data to trace in vitro productively infected cells to their original pre-infected states.

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Manganaro L, Hong P, Hernandez MM, Argyle D, Mulder LCF, Potla U, et al. IL-15 regulates susceptibility of CD4(+) T cells to HIV infection. Proc Natl Acad Sci U S A. 2018;115(41):E9659–67. https://doi.org/10.1073/pnas.1806695115.

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Luo X, Frouard J, Zhang G, Neidleman J, Xie G, Sheedy E, et al. Subsets of tissue CD4 T cells display different susceptibilities to HIV infection and death: analysis by CyTOF and single cell RNA-seq. Front Immunol. 2022;13:883420. https://doi.org/10.3389/fimmu.2022.883420.

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Xie G, Luo X, Ma T, Frouard J, Neidleman J, Hoh R, et al. Characterization of HIV-induced remodeling reveals differences in infection susceptibility of memory CD4(+) T cell subsets in vivo. Cell Rep. 2021;35(4):109038. https://doi.org/10.1016/j.celrep.2021.109038.

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Matheson NJ, Sumner J, Wals K, Rapiteanu R, Weekes MP, Vigan R, et al. Cell surface proteomic map of HIV infection reveals antagonism of amino acid metabolism by Vpu and Nef. Cell Host Microbe. 2015;18(4):409–23. https://doi.org/10.1016/j.chom.2015.09.003.

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Ross TM, Oran AE, Cullen BR. Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein. Curr Biol. 1999;9(12):613–21.

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Kaczmarek Michaels K, Natarajan M, Euler Z, Alter G, Viglianti G, Henderson AJ. Blimp-1, an intrinsic factor that represses HIV-1 proviral transcription in memory CD4+ T cells. J Immunol. 2015;194(7):3267–74. https://doi.org/10.4049/jimmunol.1402581.

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Kuo HH, Ahmad R, Lee GQ, Gao C, Chen HR, Ouyang Z, et al. Anti-apoptotic protein BIRC5 maintains survival of HIV-1-infected CD4(+) T cells. Immunity. 2018;48(6):1183–94.e5. https://doi.org/10.1016/j.immuni.2018.04.004.

Garcia JV, Miller AD. Serine phosphorylation-independent downregulation of cell-surface CD4 by nef. Nature. 1991;350(6318):508–11. https://doi.org/10.1038/350508a0.

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Arganaraz ER, Schindler M, Kirchhoff F, Cortes MJ, Lama J. Enhanced CD4 down-modulation by late stage HIV-1 nef alleles is associated with increased Env incorporation and viral replication. J Biol Chem. 2003;278(36):33912–9. https://doi.org/10.1074/jbc.M303679200.

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Alsahafi N, Ding S, Richard J, Markle T, Brassard N, Walker B, et al. Nef Proteins from HIV-1 Elite controllers are inefficient at preventing antibody-dependent cellular cytotoxicity. J Virol. 2015;90(6):2993–3002. https://doi.org/10.1128/JVI.02973-15.

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Bromley SK, Yan S, Tomura M, Kanagawa O, Luster AD. Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J Immunol. 2013;190(3):970–6. https://doi.org/10.4049/jimmunol.1202805.

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Baeyens A, Fang V, Chen C, Schwab SR. Exit strategies: S1P signaling and T cell migration. Trends Immunol. 2015;36(12):778–87. https://doi.org/10.1016/j.it.2015.10.005.

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Xiao H, Woods EC, Vukojicic P, Bertozzi CR. Precision glycocalyx editing as a strategy for cancer immunotherapy. Proc Natl Acad Sci U S A. 2016;113(37):10304–9. https://doi.org/10.1073/pnas.1608069113.

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Colomb F, Giron LB, Kuri-Cervantes L, Adeniji OS, Ma T, Dweep H, et al. Sialyl-Lewis(X) Glycoantigen is enriched on cells with persistent HIV transcription during therapy. Cell Rep. 2020;32(5):107991. https://doi.org/10.1016/j.celrep.2020.107991.

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Hsiao F, Frouard J, Gramatica A, Xie G, Telwatte S, Lee GQ, et al. Tissue memory CD4+ T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection. PLoS Pathog. 2020;16(4):e1008450. https://doi.org/10.1371/journal.ppat.1008450.

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Yukl SA, Kaiser P, Kim P, Telwatte S, Joshi SK, Vu M, et al. HIV latency in isolated patient CD4(+) T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing. Sci Transl Med. 2018;10(430):eaap9927. https://doi.org/10.1126/scitranslmed.aap9927.

Estes JD, Kityo C, Ssali F, Swainson L, Makamdop KN, Del Prete GQ, et al. Defining total-body AIDS-virus burden with implications for curative strategies. Nat Med. 2017;23(11):1271–6. https://doi.org/10.1038/nm.4411.

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Das B, Dobrowolski C, Luttge B, Valadkhan S, Chomont N, Johnston R, et al. Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir. Proc Natl Acad Sci U S A. 2018;115(33):E7795–804. https://doi.org/10.1073/pnas.1803468115.

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Scully EP, Gandhi M, Johnston R, Hoh R, Lockhart A, Dobrowolski C, et al. Sex-based differences in HIV-1 reservoir activity and residual immune activation. J Infect Dis. 2018. https://doi.org/10.1093/infdis/jiy617.

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Petkov S, Bekele Y, Lakshmikanth T, Hejdeman B, Zazzi M, Brodin P, et al. High CD45 expression of CD8+ and CD4+ T cells correlates with the size of HIV-1 reservoir in blood. Sci Rep. 2020;10(1):20425. https://doi.org/10.1038/s41598-020-77433-z.

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Bekele Y, Lakshmikanth T, Chen Y, Mikes J, Nasi A, Petkov S, et al. Mass cytometry identifies distinct CD4+ T cell clusters distinguishing HIV-1-infected patients according to antiretroviral therapy initiation. JCI Insight. 2019;4(3):e125442. https://doi.org/10.1172/jci.insight.125442.

Coindre S, Tchitchek N, Alaoui L, Vaslin B, Bourgeois C, Goujard C, et al. Mass cytometry analysis reveals the landscape and dynamics of CD32a(+) CD4(+) T cells from early HIV infection to effective cART. Front Immunol. 2018;9:1217. https://doi.org/10.3389/fimmu.2018.01217.

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• Buggert M, Nguyen S, Salgado-Montes de Oca G, Bengsch B, Darko S, Ransie A, et al. Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue. Sci Immunol. 2018;3(24):eaar4526. https://doi.org/10.1126/sciimmunol.aar4526This study identified and characterized HIV-specific resident memory CD8+ T cells in human lymphoid tissue.

Wendel BS, Del Alcazar D, He C, Del Rio-Estrada PM, Aiamkitsumrit B, Ablanedo-Terrazas Y, et al. The receptor repertoire and functional profile of follicular T cells in HIV-infected lymph nodes. Sci Immunol. 2018;3(22):eaan8884. https://doi.org/10.1126/sciimmunol.aan8884.

He C, Malone MJ, Wendel BS, Ma KY, Del Alcazar D, Weiner DB, et al. Transcriptome and TCR repertoire measurements of CXCR3(+) T follicular helper cells within HIV-infected human lymph nodes. Front Immunol. 2022;13:859070. https://doi.org/10.3389/fimmu.2022.859070.

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Coindre S, Tchitchek N, Alaoui L, Vaslin B, Bourgeois C, Goujard C, et al. Mass cytometry analysis reveals complex cell-state modifications of blood myeloid cells during HIV infection. Front Immunol. 2019;10:2677. https://doi.org/10.3389/fimmu.2019.02677.

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Zhao NQ, Vendrame E, Ferreira AM, Seiler C, Ranganath T, Alary M, et al. Natural killer cell phenotype is altered in HIV-exposed seronegative women. PLoS One. 2020;15(9):e0238347. https://doi.org/10.1371/journal.pone.0238347.

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Ivison GT, Vendrame E, Martinez-Colon GJ, Ranganath T, Vergara R, Zhao NQ, et al. Natural killer cell receptors and ligands are associated with markers of HIV-1 persistence in chronically infected ART suppressed patients. Front Cell Infect Microbiol. 2022;12:757846. https://doi.org/10.3389/fcimb.2022.757846.

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Vendrame E, Seiler C, Ranganath T, Zhao NQ, Vergara R, Alary M, et al. TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells. AIDS. 2020;34(6):801–13. https://doi.org/10.1097/QAD.0000000000002488.

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•• Strauss-Albee DM, Fukuyama J, Liang EC, Yao Y, Jarrell JA, Drake AL, et al. Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility. Sci Transl Med. 2015;7(297):297ra115. https://doi.org/10.1126/scitranslmed.aac5722. This study demonstrated that increased NK cell diversity increases susceptibility to HIV infection.

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Guilliams M, Bruhns P, Saeys Y, Hammad H, Lambrecht BN. The function of Fcgamma receptors in dendritic cells and macrophages. Nat Rev Immunol. 2014;14(2):94–108. https://doi.org/10.1038/nri3582.

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Zhao NQ, Ferreira AM, Grant PM, Holmes S, Blish CA. Treated HIV Infection alters phenotype but not HIV-specific function of peripheral blood natural killer cells. Front Immunol. 2020;11:829. https://doi.org/10.3389/fimmu.2020.00829.

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