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Although the per\u2010contact risk of penile HIV acquisition is generally low, substantial global discrepancies in HIV prevalence still exist, particularly in low\u2010income regions. In uncircumcised men, the immune milieu of the subpreputial space is a key determinant of HIV risk, with inflammation\u2010mediated epithelial disruption and target cell recruitment facilitating viral infection. Specific bacterial components of the penile microbiome cause local inflammation and enhance susceptibility, while penile circumcision reduces HIV risk by both removing susceptible foreskin tissues and reducing the abundance of these bacteria. The penile urethra is also an important site of HIV acquisition, particularly among circumcised men, but determinants of urethral susceptibility remain poorly understood. Penile\u2010vaginal sex induces transient inflammation and epithelial damage at both the subpreputial space and urethra, likely mediated by mechanical effects and\/or the sexual exchange of pro\u2010inflammatory bacteria. This review summarizes knowledge regarding the immunological and microbial determinants of penile HIV acquisition risk, highlights biological factors and sexual practices that shape the penile immune milieu, and discusses current advances in microbiome\u2010targeting interventions as potential HIV prevention strategies.<\/jats:p>","DOI":"10.1111\/aji.70266","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:12:56Z","timestamp":1783606376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HIV Transmission and Immunology of the Male Reproductive Tract"],"prefix":"10.1111","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2951-7121","authenticated-orcid":false,"given":"Jinny","family":"Tsang","sequence":"first","affiliation":[{"name":"Department of Immunology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5898-7192","authenticated-orcid":false,"given":"Rachel","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rameen","family":"Jamil","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald Moses","family":"Galiwango","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Toronto  Toronto Ontario Canada"},{"name":"Rakai Health Sciences Program  Kalisizo Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Okech","sequence":"additional","affiliation":[{"name":"International AIDS Vaccine Initiative Uganda Virus Research Institute  Entebbe Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanja","family":"Huibner","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcio Gabriel A.","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Institute of Medical Science University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lane B.","family":"Buchanan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Schulich School of Medicine and Dentistry Western University of Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy M.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health Milken Institute School of Public Health George Washington University  Washington, D.C. 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