Persistent CD8+ T cell-driven immune dysregulation despite normalized CD4+ T cell recovery in ART-treated people living with HIV

Persistent CD8+ T cell-driven immune dysregulation despite normalized CD4+ T cell recovery in ART-treated people living with HIV | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Persistent CD8 + T cell-driven immune dysregulation despite normalized CD4 + T cell recovery in ART-treated people living with HIV Yiyao Hu, Lingyun Ge, Yun He, Xiaorui Li, Yinsong Luo, Hui Wu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7284327/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Despite successful antiretroviral therapy (ART) that restores CD4⁺ T cell counts and reduces HIV viral loads to undetectable levels, a substantial proportion of people living with HIV (PLWH) exhibit persistent CD4/CD8 ratio inversion. This abnormal ratio is primarily driven by sustained CD8⁺ T cell expansion and reflects a state of chronic immune dysregulation and incomplete immune recovery. However, cellular and molecular mechanisms underlying this discordant immune state remain poorly understood. Methods We analyzed longitudinal data of 5,416 ART-treated PLWH from Shenzhen Third People’s Hospital, identifying distinct CD8⁺ T cell trajectory groups using group-based trajectory modeling. We compared those with chronic stable activation (CSA group) versus those with immune modulation recovery (IMR group) using CyTOF-based immunophenotyping, bulk RNA sequencing, and plasma biomarker profiling. Results Both IMR and CSA groups achieved CD4⁺ T cell recovery, but CSA group exhibited persistently elevated CD8⁺ T cells and inverted CD4/CD8 ratios. The CSA group displayed a marked expansion of senescent and activated CD8⁺ T cell subsets and diminished regulatory T cells, characterized by decreased expression of CD196, CD95, and CD27. Bulk RNA sequencing revealed upregulation of interferon-stimulated genes, chemokine signaling pathways and pro-inflammatory transcriptional programs. Consistently, systemic levels of key inflammatory mediators, including IP-10, MCP-1, and soluble CD163, were significantly elevated in the CSA group. Conclusion Persistent CD8⁺ T cell activation reflects a distinct immunological state marked by CD4/CD8 ratio inversion, cell senescence, exhaustion, and systemic inflammation. This immune profile may help identify individuals at increased risk of non-AIDS complications and supports the rationale for targeting CD8⁺ T cell-driven immune dysregulation to improve long-term immune restoration. HIV antiretroviral therapy CD8+ T cells CD4/CD8 ratio immune dysregulation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations Tables are available in the Supplementary Files section. Supplementary Files Table.docx SupplementalFigures.docx SupplementalTable.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7284327","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507475466,"identity":"b153156c-1e68-4fff-a16d-a1bad05a9226","order_by":0,"name":"Yiyao Hu","email":"","orcid":"","institution":"Shenzhen University","correspondingAuthor":false,"prefix":"","firstName":"Yiyao","middleName":"","lastName":"Hu","suffix":""},{"id":507475467,"identity":"275a94ea-a9f6-47bb-9990-bffb946b2b2b","order_by":1,"name":"Lingyun Ge","email":"","orcid":"","institution":"Shenzhen Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lingyun","middleName":"","lastName":"Ge","suffix":""},{"id":507475468,"identity":"7706c7cf-f96b-42e0-a61b-ea78aa4e0499","order_by":2,"name":"Yun He","email":"","orcid":"","institution":"Shenzhen Third People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"He","suffix":""},{"id":507475469,"identity":"f433b911-a875-4e0d-921b-a6c86b9e382d","order_by":3,"name":"Xiaorui Li","email":"","orcid":"","institution":"Shenzhen University","correspondingAuthor":false,"prefix":"","firstName":"Xiaorui","middleName":"","lastName":"Li","suffix":""},{"id":507475470,"identity":"738488a9-0865-42ea-a5aa-a44acb685502","order_by":4,"name":"Yinsong Luo","email":"","orcid":"","institution":"Shenzhen University","correspondingAuthor":false,"prefix":"","firstName":"Yinsong","middleName":"","lastName":"Luo","suffix":""},{"id":507475471,"identity":"074e968f-9330-476b-87e0-f35ad52544c0","order_by":5,"name":"Hui Wu","email":"","orcid":"","institution":"Shenzhen University","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Wu","suffix":""},{"id":507475472,"identity":"b5d58efc-acc6-44a3-be6a-898df8654e5a","order_by":6,"name":"Jiayi He","email":"","orcid":"","institution":"Shenzhen University","correspondingAuthor":false,"prefix":"","firstName":"Jiayi","middleName":"","lastName":"He","suffix":""},{"id":507475473,"identity":"c2c7280c-b0f8-4664-aa12-693e664bc42f","order_by":7,"name":"Chao Zhang","email":"","orcid":"","institution":"Chinese People's Liberation Army General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Zhang","suffix":""},{"id":507475474,"identity":"450b7603-2cbd-444b-9fe4-6702799dd532","order_by":8,"name":"Jiaye Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIie2ROwrCQBBARwK7FkvSpjJXmBBQweBZEoS1SRF7UUGIjVh7DEGwFgdzBgsLQbAOCCIoYlIErNyUgvuqGZjH/AA0mh/ENAAwyAPGp1vM0O8qFVYqpkiDwTKWPbVSBg07wqvIdrWJUuEC49OQGsyW4drHrQGc9qvvgwnEICWPiTN5ER5NEFIe1AqjMOFS5srFAFs0KygvGicQtR5tpNqkkhImFLB6hB5UU1iM4aLvJvmR3TnKHlPtYlm0ce+3juPM8lfen37X4pR+VYpGCDD9SBXlBcYJYFShTqPRaP6WNzG2RHIrfJqKAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-2863-7006","institution":"Shenzhen University","correspondingAuthor":true,"prefix":"","firstName":"Jiaye","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-08-03 15:45:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7284327/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7284327/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90655106,"identity":"54c9bac6-e172-4281-a97d-05e5caeebc6c","added_by":"auto","created_at":"2025-09-05 09:44:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":633105,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of participants enrolled in this study. \u003c/strong\u003e(a-b) Flow chart of participants enrolled in this study and the approach implemented by group-based trajectory modeling (GBTM) was used to identify subgroups within each group that shared a similar underlying trajectory of CD8\u003csup\u003e+\u003c/sup\u003e T cell counts. Abbreviations: IMR, Immune Modulation Recovery; CSA, Chronic Stable Activation.\u0026nbsp;\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/9021978c59852801dd39e2f4.png"},{"id":90655112,"identity":"c96d35db-dfb1-4489-a301-a3022888b621","added_by":"auto","created_at":"2025-09-05 09:44:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":495102,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe dynamic trajectory of immune recovery in PLWH.\u003c/strong\u003e (a) The dynamic variation of CD4\u003csup\u003e+\u003c/sup\u003e T cell counts in PLWH after ART based on the dynamic grouping of CD8\u003csup\u003e+\u003c/sup\u003e T cell counts. (b) The dynamic variation of CD4/CD8 ratio in PLWH after ART based on the dynamic grouping of CD8\u003csup\u003e+\u003c/sup\u003e T cell counts. Abbreviations: IMR, Immune Modulation Recovery; CSA, Chronic Stable Activation.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/c253ce20ed358b8d2c059d12.png"},{"id":90655111,"identity":"3b90a960-1e08-4175-8a16-b8dc327d6022","added_by":"auto","created_at":"2025-09-05 09:44:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":378183,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInflammatory profile.\u003c/strong\u003e Differences between groups in inflammation-related markers represented by the color legend as a fold change (CSA compared IMR). Mann-Whitney tests were performed to compare the distribution of the variables between groups IMR vs. CSA. Each dot represents one donor. Bars indicate median values; when statistically significant, p-values are indicated as *p \u0026lt; 0.05, ** p \u0026lt; 0.01) or ***p \u0026lt; 0.001. Abbreviations: IMR, Immune Modulation Recovery; CSA, Chronic Stable Activation; CRP, C-reactive protein; IFN, interferon; IL, interleukin; IP-10, interferon-g-inducible protein 10; MCP1, monocyte chemoattractant protein-1; FABP2, fatty acid-binding protein 2.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/fed0237ceb943c50d6a6da85.png"},{"id":90655375,"identity":"cb6ac3dc-be7f-4fa2-878a-7f139ce4eddf","added_by":"auto","created_at":"2025-09-05 09:52:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1261361,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePhenotypical characterization of immune populations in PLWH.\u003c/strong\u003e (a) Heatmap showing the median metal intensity of individual markers for each cluster as indicated. (b) T-SNE projection of PBMCs showing major cell populations based on expression of cell type-specific makers. Each dot corresponds to a single cell and colored according to PhenoGraph clustering (left); groups are each colored as indicated (right). (c) Frequency of all populations between the IMR and CSA groups. (d) Frequencies of immune cell populations from individuals with chronic IMR group and CSA group. Groups are shown in different colors. Significant differences are indicated by *P\u0026lt;0.05. Differences between each group were analyzed using a two-sided unpaired Mann–Whitney U-test.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/89aba815fd07e12fc8e6c35d.png"},{"id":90655113,"identity":"c5c1d871-8c8f-4b1f-9f62-81c37347dc62","added_by":"auto","created_at":"2025-09-05 09:44:36","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2603660,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCharacterization of immune cells clusters from PBMCs of IMR and CSA.\u003c/strong\u003e (a) Heatmap showing the median metal intensity of individual markers for each cluster as indicated. (b) T-SNE projection of PBMCs showing major cell clusters based on expression of cell type-specific makers. Each dot corresponds to a single cell and colored according to PhenoGraph clustering (left); groups are each colored as indicated (right). (c) Frequencies of CD8\u003csup\u003e+\u003c/sup\u003e T cell clusters from individuals with chronic IMR group and CSA group. Groups are shown in different colors. Significant differences are indicated by *P \u0026lt; 0.05. Differences between each group were analyzed using a two-sided unpaired Mann-Whitney U-test.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/ade05510e5516f19fb19ffdb.png"},{"id":90655127,"identity":"4c28e2fc-6cbe-4e1a-a461-8f4ea91005f4","added_by":"auto","created_at":"2025-09-05 09:44:36","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":513905,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunctional characterization of immune cell subsets in PLWH.\u003c/strong\u003e (a-e) Histogram showing the expression distribution of selected cell markers of CD8\u003csup\u003e +\u003c/sup\u003e Tna cells, CD8\u003csup\u003e +\u003c/sup\u003e Tef cells, CD8\u003csup\u003e +\u003c/sup\u003e Tcm cells, CD8\u003csup\u003e +\u003c/sup\u003e Tex cells, and CD8\u003csup\u003e +\u003c/sup\u003e Tem cells among the two groups. Significant differences are indicated by *P\u0026lt;0.05. Differences between each group were analyzed using a two-sided unpaired Mann–Whitney U-test.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/21dde931ef3d855a4fe373a1.png"},{"id":90656484,"identity":"7757ce44-27ba-489e-9bcb-7ca59b68ab96","added_by":"auto","created_at":"2025-09-05 10:08:44","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":988550,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImmuno-inflammatory and chemokine pathways highly expressed in CSA.\u003c/strong\u003e (a) PCA showing the significant difference in gene expression between the two groups, with the left side representing 5 cases of PLWH in the IMR group and the right side representing 5 cases of PLWH in the CSA group. (b) Volcano plot showing differentially expressed genes between the two groups, with green representing down-regulated genes, red representing up-regulated genes and grey representing no differentially expressed genes. (c) Heat map showing overall level of differentially expressed genes between the two groups. (d) KEGG enrichment analysis showing the highest expressed relevant pathways in the CSA group. (e) GSEA analysis showing chemokine signaling pathway (left), cytokine-cytokine receptor interaction (middle), PPAR (right) signaling pathway enrichment results. (f)\u003cstrong\u003e \u003c/strong\u003eGO enrichment analysis showing the most highly expressed biological processes in the CSA group. (g) GSEA analysis showing inflammatory response (left), T-cell differentiation (middle), and chemotaxis (right) enrichment results.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/36719ddc9bc0c536569f61fb.png"},{"id":93951304,"identity":"e86824c7-f7ae-4457-847a-de03d2bcc390","added_by":"auto","created_at":"2025-10-20 15:08:23","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2376359,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1_covered_467f4d2b-a519-4765-99a4-a414d0d770f9.pdf"},{"id":90655372,"identity":"44893974-0078-4456-a41b-9add24faa0cc","added_by":"auto","created_at":"2025-09-05 09:52:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24479,"visible":true,"origin":"","legend":"","description":"","filename":"Table.docx","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/84a37a1bf0b19738923d24a8.docx"},{"id":90655133,"identity":"101ae86d-dd94-43e4-a1d4-bca2b25ad94e","added_by":"auto","created_at":"2025-09-05 09:44:37","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":22547475,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/533c2b45538e001a2f06dbd4.docx"},{"id":90655373,"identity":"7d22883c-0f62-4e8e-8738-cd1bed48cde9","added_by":"auto","created_at":"2025-09-05 09:52:36","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":20804,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7284327/v1/6d6b2fff08971450c747c0b5.docx"}],"financialInterests":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e","formattedTitle":"\u003cp\u003ePersistent CD8\u003csup\u003e+\u003c/sup\u003e T cell-driven immune dysregulation despite normalized CD4\u003csup\u003e+\u003c/sup\u003e T cell recovery in ART-treated people living with HIV\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HIV, antiretroviral therapy, CD8+ T cells, CD4/CD8 ratio, immune dysregulation","lastPublishedDoi":"10.21203/rs.3.rs-7284327/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7284327/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eDespite successful antiretroviral therapy (ART) that restores CD4⁺ T cell counts and reduces HIV viral loads to undetectable levels, a substantial proportion of people living with HIV (PLWH) exhibit persistent CD4/CD8 ratio inversion. This abnormal ratio is primarily driven by sustained CD8⁺ T cell expansion and reflects a state of chronic immune dysregulation and incomplete immune recovery. However, cellular and molecular mechanisms underlying this discordant immune state remain poorly understood.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe analyzed longitudinal data of 5,416 ART-treated PLWH from Shenzhen Third People\u0026rsquo;s Hospital, identifying distinct CD8⁺ T cell trajectory groups using group-based trajectory modeling. We compared those with chronic stable activation (CSA group) versus those with immune modulation recovery (IMR group) using CyTOF-based immunophenotyping, bulk RNA sequencing, and plasma biomarker profiling.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eBoth IMR and CSA groups achieved CD4⁺ T cell recovery, but CSA group exhibited persistently elevated CD8⁺ T cells and inverted CD4/CD8 ratios. The CSA group displayed a marked expansion of senescent and activated CD8⁺ T cell subsets and diminished regulatory T cells, characterized by decreased expression of CD196, CD95, and CD27. Bulk RNA sequencing revealed upregulation of interferon-stimulated genes, chemokine signaling pathways and pro-inflammatory transcriptional programs. Consistently, systemic levels of key inflammatory mediators, including IP-10, MCP-1, and soluble CD163, were significantly elevated in the CSA group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePersistent CD8⁺ T cell activation reflects a distinct immunological state marked by CD4/CD8 ratio inversion, cell senescence, exhaustion, and systemic inflammation. This immune profile may help identify individuals at increased risk of non-AIDS complications and supports the rationale for targeting CD8⁺ T cell-driven immune dysregulation to improve long-term immune restoration.\u003c/p\u003e","manuscriptTitle":"Persistent CD8+ T cell-driven immune dysregulation despite normalized CD4+ T cell recovery in ART-treated people living with HIV","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-05 09:44:31","doi":"10.21203/rs.3.rs-7284327/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cc800027-961d-45ad-b3f0-88cc07187d22","owner":[],"postedDate":"September 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T15:00:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-05 09:44:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7284327","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7284327","identity":"rs-7284327","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}