Single-cell RNA sequencing reveals the diversity of the immunological landscape response to genital herpes

Siji Chen; Jiang Zhu; Chunting Hua; Chenxi Feng; Xia Wu; Can Zhou; Xianzhen Chen; Boya Zhang; Yaohan Xu; Zeyu Ma; Jianping He; Na Jin; Yinjing Song; Stijn van der Veen; Hao Cheng

doi:10.1016/j.virs.2024.10.003

December 2024

. doi: 10.1016/j.virs.2024.10.003

Citation: Siji Chen, Jiang Zhu, Chunting Hua, Chenxi Feng, Xia Wu, Can Zhou, Xianzhen Chen, Boya Zhang, Yaohan Xu, Zeyu Ma, Jianping He, Na Jin, Yinjing Song, Stijn van der Veen, Hao Cheng. Single-cell RNA sequencing reveals the diversity of the immunological landscape response to genital herpes .VIROLOGICA SINICA, 2024, 39(6) : 860-874. http://dx.doi.org/10.1016/j.virs.2024.10.003

单细胞RNA测序揭示机体对生殖器疱疹免疫景观的多样性

陈思吉 ^a ,
朱江 ^a ,
华春婷 ^a ,
冯晨希 ^a ,
吴霞 ^a ,
周灿 ^a ,
陈贤祯 ^a ,
张博雅 ^a ,
许瑶函 ^a ,
马泽宇 ^a ,
何剑萍 ^a ,
金纳 ^a ,
宋寅敬 ^a,, ,
Stijn van der Veena ^a,b,, ,
程浩 ^a,,

cstr: 32224.14.j.virs.2024.10.003

a. 浙江大学医学院附属邵逸夫医院, 皮肤科, 杭州 310016;
b. 浙江大学医学院微生物学系, 感染性疾病诊治协同创新中心, 杭州 310058

通讯作者： 宋寅敬, 3315023@zju.edu.cn; Stijn van der Veena, stijnvanderveen@zju.edu.cn; 程浩, chenghao1@zju.edu.cn
收稿日期： 2024-04-22
录用日期： 2024-10-12

摘要

生殖器疱疹（GH）是一种常见的性传播疾病，主要由单纯疱疹病毒2型（HSV-2）引起，目前仍然是一个重要的全球健康问题。尽管我们对GH患者免疫细胞群体变化和免疫调节的理解仍然有限，但很明显在HSV-2感染和GH复发过程中，系统固有免疫、先天免疫和适应性免疫发挥着重要作用。为了研究HSV-2感染和复发的机制，我们对从健康个体和复发性GH患者外周血中分离出的免疫细胞进行了单细胞RNA测序(scRNA-seq)。此外，复发性GH患者的系统免疫反应显示了经典单核细胞、CD4⁺ T细胞、自然杀伤细胞（NK细胞）和浆细胞样树突状细胞的激活，特别是与 Toll 样受体信号通路和T细胞活化相关的基因的激活。在scRNA-seq数据集以及独立的定量实时聚合酶链式反应（qRT-PCR）分析和ELISA实验中，GH患者循环免疫细胞显示出与炎症和抗病毒反应相关基因的高表达。本研究表明，由HSV再激活引起的局部生殖器疱疹可能影响循环免疫细胞的功能，这提示了未来研究HSV感染和复发期间系统免疫作用的潜在方向。
- 单细胞转录组学
- , 生殖器疱疹
- , 单纯疱疹病毒
- , 免疫反应

Single-cell RNA sequencing reveals the diversity of the immunological landscape response to genital herpes

Siji Chen ^a ,
Jiang Zhu ^a ,
Chunting Hua ^a ,
Chenxi Feng ^a ,
Xia Wu ^a ,
Can Zhou ^a ,
Xianzhen Chen ^a ,
Boya Zhang ^a ,
Yaohan Xu ^a ,
Zeyu Ma ^a ,
Jianping He ^a ,
Na Jin ^a ,
Yinjing Song ^a,, ,
Stijn van der Veen ^a,b,, ,
Hao Cheng ^a,,

a. Department of Dermatology and Venereology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China;
b. Department of Microbiology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou 310058, China

Corresponding author: Yinjing Song, 3315023@zju.edu.cn Stijn van der Veen, stijnvanderveen@zju.edu.cn Hao Cheng, chenghao1@zju.edu.cn
Received Date: 22 April 2024
Accepted Date: 12 October 2024

Abstract

Genital herpes (GH) is a common sexually transmitted disease, which is primarily caused by herpes simplex virus type 2 (HSV-2), and continues to be a global health concern. Although our understanding of the alterations in immune cell populations and immunomodulation in GH patients is still limited, it is evident that systemic intrinsic immunity, innate immunity, and adaptive immunity play crucial roles during HSV-2 infection and GH reactivation. To investigate the mechanisms underlying HSV-2 infection and recurrence, single-cell RNA sequencing (scRNA-seq) was performed on immune cells isolated from the peripheral blood of both healthy individuals and patients with recurrent GH. Furthermore, the systemic immune response in patients with recurrent GH showed activation of classical monocytes, CD4⁺ T cells, natural killer cells (NK cells), and plasmacytoid dendritic cells (pDCs), especially of genes associated with the Toll-like receptor signaling pathway and T cell activation. Circulating immune cells in GH patients show higher expression of genes associated with inflammation and antiviral responses both in the scRNA-Seq data set and in independent quantitative real-time polymerase chain reaction (qRT-PCR) analysis and ELISA experiments. This study demonstrated that localized genital herpes, resulting from HSV reactivation, may influence the functionality of circulating immune cells, suggesting a potential avenue for future research into the role of systemic immunity during HSV infection and recurrence.
- Single-cell RNA sequencing (scRNA-seq)
- , Genital herpes (GH)
- , Herpes simplex virus (HSV)
- , Immune response

References
1. Adachi, A., Honda, T., Dainichi, T., Egawa, G., Yamamoto, Y., Nomura, T., Nakajima, S., Otsuka, A., Maekawa, M., Mano, N., Koyanagi, N., Kawaguchi, Y., Ohteki, T., Nagasawa, T., Ikuta, K., Kitoh, A., Kabashima, K., 2021. Prolonged high-intensity exercise induces fluctuating immune responses to herpes simplex virus infection via glucocorticoids. Journal of Allergy and Clinical Immunology 148, 1575-1588.e7.
2. Alcantara-Hernandez, M., Leylek, R., Wagar, L.E., Engleman, E.G., Keler, T., Marinkovich, M.P., Davis, M.M., Nolan, G.P., Idoyaga, J., 2017. High-Dimensional Phenotypic Mapping of Human Dendritic Cells Reveals Interindividual Variation and Tissue Specialization. Immunity 47, 1037-1050.e6.
3. Aran, D., Looney, A.P., Liu, L., Wu, E., Fong, V., Hsu, A., Chak, S., Naikawadi, R.P., Wolters, P.J., Abate, A.R., Butte, A.J., Bhattacharya, M., 2019. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol 20, 163-172.
4. Arduino, P.G., Porter, S.R., 2008. Herpes Simplex Virus Type 1 infection: overview on relevant clinico-pathological features. Journal of Oral Pathology & Medicine 37, 107-121.
5. Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D., Butler, H., Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T., Harris, M.A., Hill, D.P., Issel-Tarver, L., Kasarskis, A., Lewis, S., Matese, J.C., Richardson, J.E., Ringwald, M., Rubin, G.M., Sherlock, G., 2000. Gene Ontology: tool for the unification of biology. Nat Genet 25, 25-29.
6. Bianchini, M., Duchene, J., Santovito, D., Schloss, M.J., Evrard, M., Winkels, H., Aslani, M., Mohanta, S.K., Horckmans, M., Blanchet, X., Lacy, M., von Hundelshausen, P., Atzler, D., Habenicht, A., Gerdes, N., Pelisek, J., Ng, L.G., Steffens, S., Weber, C., Megens, R.T.A., 2019. PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function. Sci Immunol 4, eaar3054.
7. Birzer, A., Krawczyk, A., Drassner, C., Kuhnt, C., Muhl-Zurbes, P., Heilingloh, C.S., Steinkasserer, A., Popella, L., 2020. HSV-1 Modulates IL-6 Receptor Expression on Human Dendritic Cells. Front Immunol 11. https://doi.org/10.3389/fimmu.2020.01970.
8. Butler, A., Hoffman, P., Smibert, P., Papalexi, E., Satija, R., 2018. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 36, 411-420.
9. Cao, W., Bover, L., 2010. Signaling and ligand interaction of ILT7: receptor-mediated regulatory mechanisms for plasmacytoid dendritic cells. Immunol Rev 234, 163-176.
10. Carty, M., Reinert, L., Paludan, S.R., Bowie, A.G., 2014. Innate antiviral signalling in the central nervous system. Trends Immunol 35, 79-87.
11. Chen, Y.-L., Gomes, T., Hardman, C.S., Vieira Braga, F.A., Gutowska-Owsiak, D., Salimi, M., Gray, N., Duncan, D.A., Reynolds, G., Johnson, D., Salio, M., Cerundolo, V., Barlow, J.L., McKenzie, A.N.J., Teichmann, S.A., Haniffa, M., Ogg, G., 2020. Re-evaluation of human BDCA-2+ DC during acute sterile skin inflammation. Journal of Experimental Medicine 217, jem.20190811.
12. Choi, K., Raghupathy, N., Churchill, G.A., 2019. A Bayesian mixture model for the analysis of allelic expression in single cells. Nat Commun 10, 5188.
13. Cliffe, A.R., Arbuckle, J.H., Vogel, J.L., Geden, M.J., Rothbart, S.B., Cusack, C.L., Strahl, B.D., Kristie, T.M., Deshmukh, M., 2015. Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation. Cell Host Microbe 18, 649-658.
14. Collins, N., Hochheiser, K., Carbone, F.R., Gebhardt, T., 2017. Sustained accumulation of antigen-presenting cells after infection promotes local T-cell immunity. Immunol Cell Biol 95, 878-883.
15. Corey, L., Handsfield, H.H., 2000. Genital Herpes and Public Health. JAMA 283, 791.
16. Coulon, P.-G., Roy, S., Prakash, S., Srivastava, R., Dhanushkodi, N., Salazar, S., Amezquita, C., Nguyen, L., Vahed, H., Nguyen, A.M., Warsi, W.R., Ye, C., Carlos-Cruz, E.A., Mai, U.T., BenMohamed, L., 2020. Upregulation of Multiple CD8+ T Cell Exhaustion Pathways Is Associated with Recurrent Ocular Herpes Simplex Virus Type 1 Infection. The Journal of Immunology 205, 454-468.
17. Danastas, K., Guo, G., Merjane, J., Hong, N., Larsen, A., Miranda-Saksena, M., Cunningham, A.L., 2023. Interferon inhibits the release of herpes simplex virus-1 from the axons of sensory neurons. mBio 14, e0181823.
18. Dhanushkodi, N.R., Prakash, S., Srivastava, R., Coulon, P.-G.A., Arellano, D., Kapadia, R. V., Fahim, R., Suzer, B., Jamal, L., Vahed, H., BenMohamed, L., 2022. Antiviral CD19+ CD27+ Memory B Cells Are Associated with Protection from Recurrent Asymptomatic Ocular Herpesvirus Infection. J Virol 96, e0205721.
19. Dong-Newsom, P., Powell, N.D., Bailey, M.T., Padgett, D.A., Sheridan, J.F., 2010. Repeated social stress enhances the innate immune response to a primary HSV-1 infection in the cornea and trigeminal ganglia of Balb/c mice. Brain Behav Immun 24, 273-280.
20. Franzen-Rohl, E., Schepis, D., Lagrelius, M., Franck, K., Jones, P., Liljeqvist, J.-A., Bergstrom, T., Aurelius, E., Karre, K., Berg, L., Gaines, H., 2011. Increased Cell-Mediated Immune Responses in Patients with Recurrent Herpes Simplex Virus Type 2 Meningitis. Clinical and Vaccine Immunology 18, 655-660.
21. Freeman, E.E., Weiss, H.A., Glynn, J.R., Cross, P.L., Whitworth, J.A., Hayes, R.J., 2006. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 20, 73-83.
22. Gao, D., Ciancanelli, M.J., Zhang, P., Harschnitz, O., Bondet, V., Hasek, M., Chen, J., Mu, X., Itan, Y., Cobat, A., Sancho-Shimizu, V., Bigio, B., Lorenzo, L., Ciceri, G., McAlpine, J., Anguiano, E., Jouanguy, E., Chaussabel, D., Meyts, I., Diamond, M.S., Abel, L., Hur, S., Smith, G.A., Notarangelo, L., Duffy, D., Studer, L., Casanova, J.-L., Zhang, S.-Y., 2021. TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons. Journal of Clinical Investigation 131, e134529.
23. Garand, M., Goodier, M., Owolabi, O., Donkor, S., Kampmann, B., Sutherland, J.S., 2018. Functional and Phenotypic Changes of Natural Killer Cells in Whole Blood during Mycobacterium tuberculosis Infection and Disease. Front Immunol 9, 257.
24. Geissmann, F., Jung, S., Littman, D.R., 2003. Blood Monocytes Consist of Two Principal Subsets with Distinct Migratory Properties. Immunity 19, 71-82.
25. Groves, M.J., 2016. Genital Herpes: A Review. Am Fam Physician 93, 928-934.
26. Gupta, R., Warren, T., Wald, A., 2007. Genital herpes. The Lancet 370, 2127-2137.
27. Iijima, N., Iwasaki, A., 2016. Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature 533, 552-556.
28. Iijima, N., Iwasaki, A., 2014. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science (1979) 346, 93-98.
29. Iijima, N., Mattei, L.M., Iwasaki, A., 2011. Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue. Proceedings of the National Academy of Sciences 108, 284-289.
30. James, C., Harfouche, M., Welton, N.J., Turner, K.M., Abu-Raddad, L.J., Gottlieb, S.L., Looker, K.J., 2020. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ 98, 315-329.
31. Kanehisa, M., Furumichi, M., Sato, Y., Ishiguro-Watanabe, M., Tanabe, M., 2021. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res 49, D545-D551.
32. Khanna, K.M., Bonneau, R.H., Kinchington, P.R., Hendricks, R.L., 2003. Herpes Simplex Virus-Specific Memory CD8+ T Cells Are Selectively Activated and Retained in Latently Infected Sensory Ganglia. Immunity 18, 593-603.
33. Kumamoto, Y., Linehan, M., Weinstein, J.S., Laidlaw, B.J., Craft, J.E., Iwasaki, A., 2013. CD301b+ Dermal Dendritic Cells Drive T Helper 2 Cell-Mediated Immunity. Immunity 39, 733-743.
34. Lang, A., Nikolich-Zugich, J, 2005. Development and Migration of Protective CD8+ T Cells into the Nervous System following Ocular Herpes Simplex Virus-1 Infection. The Journal of Immunology 174, 2919-2925.
35. Lebratti, T., Lim, Y.S., Cofie, A., Andhey, P., Jiang, X., Scott, J., Fabbrizi, M.R., Ozanturk, A.N., Pham, C., Clemens, R., Artyomov, M., Dinauer, M., Shin, H., 2021. A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection. Elife 10, e65762.
36. Lenart, M., Dzialo, E., Kluczewska, A., Weglarczyk, K., Szaflarska, A., Rutkowska-Zapala, M., Surmiak, M., Sanak, M., Pituch-Noworolska, A., Siedlar, M., 2021. miRNA Regulation of NK Cells Antiviral Response in Children With Severe and/or Recurrent Herpes Simplex Virus Infections. Front Immunol 11, 589866.
37. Leylek, R., Alcantara-Hernandez, M., Lanzar, Z., Ludtke, A., Perez, O.A., Reizis, B., Idoyaga, J., 2019. Integrated Cross-Species Analysis Identifies a Conserved Transitional Dendritic Cell Population. Cell Rep 29, 3736-3750.e8.
38. Lind, L., Svensson, A., Thorn, K., Krzyzowska, M., Eriksson, K., 2021. CD8+ T cells in the central nervous system of mice with herpes simplex infection are highly activated and express high levels of CCR5 and CXCR3. J Neurovirol 27, 145-153.
39. Macleod, B.L., Bedoui, S., Hor, J.L., Mueller, S.N., Russell, T.A., Hollett, N.A., Heath, W.R., Tscharke, D.C., Brooks, A.G., Gebhardt, T., 2014. Distinct APC Subtypes Drive Spatially Segregated CD4+ and CD8+ T-Cell Effector Activity during Skin Infection with HSV-1. PLoS Pathog 10, e1004303.
40. Moss, N.J., Magaret, A., Laing, K.J., Kask, A.S., Wang, M., Mark, K.E., Schiffer, J.T., Wald, A., Koelle, D.M., 2012. Peripheral Blood CD4 T-Cell and Plasmacytoid Dendritic Cell (pDC) Reactivity to Herpes Simplex Virus 2 and pDC Number Do Not Correlate with the Clinical or Virologic Severity of Recurrent Genital Herpes. J Virol 86, 9952-9963.
41. Murray, L., Xi, Y., Upham, J.W., 2019. CLEC4C gene expression can be used to quantify circulating plasmacytoid dendritic cells. J Immunol Methods 464, 126-130.
42. Posavad, C.M., Koelle, D.M., Shaughnessy, M.F., Corey, L., 1997. Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8 + cytotoxic T lymphocyte responses. Proceedings of the National Academy of Sciences 94, 10289-10294.
43. Samudio, I., Rezvani, K., Shaim, H., Hofs, E., Ngom, M., Bu, L., Liu, G., Lee, J.T.C., Imren, S., Lam, V., Poon, G.F.T., Ghaedi, M., Takei, F., Humphries, K., Jia, W., Krystal, G., 2016. UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells. Blood 127, 2575-2586.
44. Schiffer, J.T., Corey, L., 2013. Rapid host immune response and viral dynamics in herpes simplex virus-2 infection. Nat Med 19, 280-288.
45. Schwartzkopff, F., Petersen, F., Grimm, T.A., Brandt, E., 2012. CXC chemokine ligand 4 (CXCL4) down-regulates CC chemokine receptor expression on human monocytes. Innate Immun 18, 124-139.
46. Shao, Q., Wu, F., Liu, Tong, Wang, W., Liu, Tianli, Jin, X., Xu, L., Ma, Y., Huang, G., Chen, Z., 2021. JieZe-1 Alleviates HSV-2 Infection-Induced Genital Herpes in Balb/c Mice by Inhibiting Cell Apoptosis via Inducing Autophagy. Front Pharmacol 12.
47. Sharma, D., Sharma, S., Akojwar, N., Dondulkar, A., Yenorkar, N., Pandita, D., Prasad, S.K., Dhobi, M., 2023. An Insight into Current Treatment Strategies, Their Limitations, and Ongoing Developments in Vaccine Technologies against Herpes Simplex Infections. Vaccines (Basel) 11, 206.
48. Sheth, P.M., Sunderji, S., Shin, L.Y.Y., Rebbapragada, A., Huibner, S., Kimani, J., MacDonald, K.S., Ngugi, E., Bwayo, J.J., Moses, S., Kovacs, C., Loutfy, M., Kaul, R., 2008. Coinfection with Herpes Simplex Virus Type 2 Is Associated with Reduced HIV-Specific T Cell Responses and Systemic Immune Activation. J Infect Dis 197, 1394-1401.
49. Shin, H., Kumamoto, Y., Gopinath, S., Iwasaki, A., 2016. CD301b+ dendritic cells stimulate tissue-resident memory CD8+ T cells to protect against genital HSV-2. Nat Commun 7, 13346.
50. Smith, J.B., Herbert, J.J., Truong, N.R., Cunningham, A.L., 2022. Cytokines and chemokines: The vital role they play in herpes simplex virus mucosal immunology. Front Immunol 13, 936235.
51. Sozzani, S., Vermi, W., Del Prete, A., Facchetti, F., 2010. Trafficking properties of plasmacytoid dendritic cells in health and disease. Trends Immunol 31, 270-277.
52. Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W.M., Hao, Y., Stoeckius, M., Smibert, P., Satija, R., 2019. Comprehensive Integration of Single-Cell Data. Cell 177, 1888-1902.e21.
53. Suomalainen, M., Greber, U.F., 2021. Virus Infection Variability by Single-Cell Profiling. Viruses 13, 1568.
54. Swiecki, M., Wang, Y., Gilfillan, S., Colonna, M., 2013. Plasmacytoid Dendritic Cells Contribute to Systemic but Not Local Antiviral Responses to HSV Infections. PLoS Pathog 9, e1003728.
55. Triana, S., Stanifer, M.L., Metz-Zumaran, C., Shahraz, M., Mukenhirn, M., Kee, C., Serger, C., Koschny, R., Ordonez-Rueda, D., Paulsen, M., Benes, V., Boulant, S., Alexandrov, T., 2021. Single-cell transcriptomics reveals immune response of intestinal cell types to viral infection. Mol Syst Biol 17, e9833.
56. Truong, N.R., Smith, J.B., Sandgren, K.J., Cunningham, A.L., 2019. Mechanisms of Immune Control of Mucosal HSV Infection: A Guide to Rational Vaccine Design. Front Immunol 10, 373.
57. Tuddenham, S., Hamill, M.M., Ghanem, K.G., 2022. Diagnosis and Treatment of Sexually Transmitted Infections. JAMA 327, 161.
58. Villani, A.-C., Satija, R., Reynolds, G., Sarkizova, S., Shekhar, K., Fletcher, J., Griesbeck, M., Butler, A., Zheng, S., Lazo, S., Jardine, L., Dixon, D., Stephenson, E., Nilsson, E., Grundberg, I., McDonald, D., Filby, A., Li, W., De Jager, P.L., Rozenblatt-Rosen, O., Lane, A.A., Haniffa, M., Regev, A., Hacohen, N., 2017. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 356, eaah4573.
59. Yan, C., Luo, Z., Li, W., Li, X., Dallmann, R., Kurihara, H., Li, Y.-F., He, R.-R., 2020. Disturbed Yin-Yang balance: stress increases the susceptibility to primary and recurrent infections of herpes simplex virus type 1. Acta Pharm Sin B 10, 383-398.
60. Yang, C.-A., Raftery, M.J., Hamann, L., Guerreiro, M., Grutz, G., Haase, D., Unterwalder, N., Schonrich, G., Schumann, R.R., Volk, H.-D., Scheibenbogen, C., 2012. Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis. Hum Immunol 73, 844-851.
61. Zeiner, P.S., Preusse, C., Blank, A., Zachskorn, C., Baumgarten, P., Caspary, L., Braczynski, A.K., Weissenberger, J., Bratzke, H., Reiss, S., Pennartz, S., Winkelmann, R., Senft, C., Plate, K.H., Wischhusen, J., Stenzel, W., Harter, P.N., Mittelbronn, M., 2015. MIF Receptor CD74 is Restricted to Microglia/Macrophages, Associated with a M1-Polarized Immune Milieu and Prolonged Patient Survival in Gliomas. Brain Pathology 25, 491-504.
62. Zhu, J., Koelle, D.M., Cao, J., Vazquez, J., Huang, M.L., Hladik, F., Wald, A., Corey, L., 2007. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med 204, 595-603.
Proportional views

Electronic Supplementary Material

10.1016j.virs.2024.10.003-ESM1.docx
10.1016j.virs.2024.10.003-ESM4.xlsx
10.1016j.virs.2024.10.003-ESM7.xlsx
10.1016j.virs.2024.10.003-ESM3.xlsx
10.1016j.virs.2024.10.003-ESM6.xlsx
10.1016j.virs.2024.10.003-ESM2.xlsx
10.1016j.virs.2024.10.003-ESM8.xlsx
10.1016j.virs.2024.10.003-ESM5.xlsx