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Clinical Research and Public HealthIn-Press PreviewAIDS/HIVInfectious diseaseReproductive biology Open Access | 10.1172/JCI208629

Impact of sexual debut on urethral immunology and microbiome in adolescent males from Rakai, Uganda

Rameen Jamil,1 Sanja Huibner,1 Ping Yang,2 James Nnamutete,3 Jodie L. White,2 Lori Sokoll,2 James Pollock,1 Margaret Nakalanzi,3 Simon Peter Bukenya,3 Stephen D. Kiboneka,3 Mathias Agaba,3 Mary J. Nalubowa,3 Aggrey Anok,3 Godfrey Kigozi,3 Ronald M. Galiwango,3 Bryan Coburn,1 Cindy M. Liu,4 Jessica L. Prodger,5 Aaron A.R. Tobian,2 and Rupert Kaul1

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

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1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

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1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

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1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

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1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

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1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Sokoll, L. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Pollock, J. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Nakalanzi, M. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

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1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Kiboneka, S. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Agaba, M. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Nalubowa, M. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Anok, A. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Kigozi, G. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Galiwango, R. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Coburn, B. in: PubMed | Google Scholar |

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Liu, C. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Prodger, J. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Tobian, A. in: PubMed | Google Scholar

1Department of Immunology, University of Toronto, Toronto, Canada

2Department of Pathology, The Johns Hopkins University, Baltimore, United States of America

3Rakai Health Sciences Program, Kalisizo, Uganda

4Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States of America

5Department of Microbiology and Immunology, Western University, London, Canada

Find articles by Kaul, R. in: PubMed | Google Scholar |

Published October 6, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI208629.
Copyright © 2026, Jamil et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 6, 2026 - Version history
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Abstract

BACKGROUND. The penile urethra is a primary site of HIV acquisition in males, although little is known about the urethral determinants of HIV susceptibility. Inflammation at other genital sites enhances HIV risk, and studies suggest that some inflammatory urethral bacteria may be vaginally acquired. Here, we characterize the impact of sexual debut on the microbiome and immune milieu of the penile urethra in adolescent males from Rakai, Uganda.

METHODS. A cohort of 185 self-reported sexually naïve adolescent males from Rakai, Uganda were followed longitudinally for 3 years, with questionnaires administered every 3 months and urethral swabs collected annually. Urethral soluble immune factors were quantified by chemiluminescent multiplex immunoassay and bacterial 16S rRNA sequencing was performed. Unsupervised clustering and mixed-effects models were used to assess associations between sexual debut and the urethral microbiome and immune milieu.

RESULTS. Unsupervised clustering at 36 months identified two distinct urethral Community State Types (CSTs): CST-1 was dominated by Streptococcus mitis and CST-2 by bacteria associated with bacterial vaginosis (BV), particularly Sneathia amnii and Gardnerella vaginalis. CST-2 was greatly enriched at 36 months compared to baseline and was associated strongly with sexual debut. Individual bacterial taxa enriched in CST-2 were associated with both sexual debut and elevated urethral inflammatory cytokines, independent of serum testosterone and penile circumcision status.

CONCLUSION. The penile urethra is colonized by BV-associated bacteria after penile-vaginal sex debut. Their presence in the urethra induces local inflammation and may serve as a reservoir for subsequent reintroduction into the vagina of female sexual partners.

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