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This review highlights innovative methodologies for investigating host responses to HIV infection using ex vivo human genital tissues. Recent advances in spatial transcriptomics and multiplex imaging enable high\u2010resolution analysis of tissue architecture, immune cell distribution, and gene expression within mucosal environments. These technologies reveal spatially heterogeneous immune responses as well as epithelial and submucosal structural alterations associated with increased HIV susceptibility and chronic infection. Computational workflows tailored to genital tissue morphology enhance reproducibility and support the integration of transcriptomic and imaging data. Despite current limitations, such as resolution constraints and high costs, ongoing improvements in spatial transcriptomics and bioimaging platforms promise deeper insights into mucosal barrier function and HIV pathogenesis. Characterizing tissue\u2010specific immune dynamics through these approaches may guide the development of targeted interventions aimed at reinforcing mucosal defenses and reducing vulnerability to HIV infection.<\/jats:p>","DOI":"10.1111\/aji.70240","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:10:45Z","timestamp":1777475445000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Approaches for Investigating Host Responses to HIV Infection in Ex Vivo Human Genital Tissues"],"prefix":"10.1111","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0219-3655","authenticated-orcid":false,"given":"Mathias Franz\u00e9n","family":"Boger","sequence":"first","affiliation":[{"name":"Department of Medicine Solna Division of Infectious Diseases Karolinska Institutet Department of Infectious Diseases Center For Molecular Medicine Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2485-5156","authenticated-orcid":false,"given":"Vilde","family":"Kaldhusdal","sequence":"additional","affiliation":[{"name":"Department of Medicine Solna Division of Infectious Diseases Karolinska Institutet Department of Infectious Diseases Center For Molecular Medicine Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2224-7664","authenticated-orcid":false,"given":"Kristina","family":"Broliden","sequence":"additional","affiliation":[{"name":"Department of Medicine Solna Division of Infectious Diseases Karolinska Institutet Department of Infectious Diseases Center For Molecular Medicine Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.03.005"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010023\u201001538\u20106"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08757"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105\u20102896.2005.00287.x"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002030\u2010200008180\u201000011"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1086\/315790"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1084\/JEM.20040874"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010024\u201002538\u20106"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012888"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010025\u201007871\u2010w"},{"key":"e_1_2_11_12_1","unstructured":"UNAIDS.https:\/\/www.unaids.org\/en."},{"key":"e_1_2_11_13_1","unstructured":"New guidance on ethical HIV prevention trials published.https:\/\/www.who.int\/news\/item\/27\u201001\u20102021\u2010new\u2010guidance\u2010on\u2010ethical\u2010hiv\u2010prevention\u2010trials\u2010published."},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/AJI.12520"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/OLQ.0000000000001931"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2403"},{"key":"e_1_2_11_17_1","unstructured":"FAIRsharing | Home. 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