Study Shows PrEP Does Not Alter Tight Junction Gene Expressions in Male Foreskin

Medical News: A recent study involving researchers from multiple global institutions, including the Karolinska Institutet in Sweden, Imperial College London in the UK, University of the Witwatersrand in South Africa, and others, has delved into the effects of HIV pre-exposure prophylaxis (PrEP) on male foreskin tissue. This investigation focused on whether short-term use of PrEP alters gene expression within the foreskin - particularly in genes related to tight junctions, which play a crucial role in cellular barriers.


Study Shows PrEP Does Not Alter Tight Junction Gene Expressions in Male Foreskin
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The study’s findings, gathered from the CHAPS trial in Uganda and South Africa, offer a clearer picture of how PrEP might impact tissue at the molecular level. This Medical News report presents a deep dive into the trial’s methodology, the significance of tight junction genes in HIV prevention, and why the study's findings could have broad implications for public health.
 
Tight Junctions and PrEP: What’s the Connection?
Tight junctions (TJs) are protein complexes that create a cellular seal, regulating the passage of molecules and pathogens, such as viruses, across cellular barriers. The role of these TJs is critical in the male genital tract, where they can act as a barrier against viral entry. PrEP, which uses antiretroviral medications to prevent HIV, has shown promising results in decreasing HIV transmission risk. However, the effects of PrEP on gene expression in genital tissue had yet to be fully understood.
 
In this research, the study team examined samples from 144 young male participants in the CHAPS trial who were either given PrEP or assigned to a control group before undergoing voluntary circumcision. By analyzing the expression of 132 TJ-related genes, the researchers aimed to identify any changes associated with PrEP use, specifically focusing on the proteins CLDN-1, OCLN, and ZO-1, which are pivotal in maintaining TJ integrity.
 
Methodology: Mapping Gene Expression
Using advanced RNA sequencing techniques, the researchers created a map of TJ gene expression in the foreskin samples. Gene counts were measured to observe the expression levels of various proteins that contribute to cellular barriers. Of the 132 genes studied, 118 were expressed at notably high levels, creating a comprehensive map of the foreskin’s TJ components. This article will explore how these components act as a critical line of defense against HIV-1, especially during insertive sex.
 
Further, the study also evaluated cytokine genes in the foreskin - signaling molecules that help regulate TJ proteins and may influence barrier function under inflammatory conditions. Key findings indicated high correlations between the expression of TJ genes and cytokine genes such as IL-18, IL-33, and VEGF, known to impact TJ structure and stability.
 
PrEP’s Impact on Gene Expression: Key Findings
The most noteworthy outco me of this study was that PrEP did not lead to any detectable changes in TJ gene expression within foreskin tissue. This suggests that the use of short-term PrEP does not disrupt the natural TJ structure, which is essential in preventing viral entry.
 
-Consistency Across Regions: Interestingly, while gene expression varied slightly between South African and Ugandan participants, PrEP had no significant impact on TJ gene expression in either region. Twenty-five genes displayed differences between these populations, but these were not influenced by the PrEP regimen.
Stable TJ Protein Levels: Protein levels for CLDN-1, OCLN, and ZO-1, as measured through Western blotting, remained steady across participants, regardless of PrEP exposure. This reinforces the idea that PrEP does not compromise TJ integrity, maintaining the cellular barriers that play a crucial role in preventing viral infections.
 
-Correlation with Cytokine Genes: The study also highlighted a strong positive correlation between certain cytokine and TJ genes. IL-18, VEGF, and IL-33, for instance, showed significant associations with TJ gene expression, indicating a broader regulatory network in foreskin tissue that could respond to inflammatory signals or immune responses.
 
Implications for HIV Prevention
These findings hold promise for the ongoing global efforts to prevent HIV through PrEP use. The foreskin is a major target tissue in HIV acquisition, particularly for heterosexual men; thus, understanding its molecular responses to PrEP provides essential insights into PrEP’s overall safety. Since TJ integrity remains unaffected, PrEP can be administered without the risk of weakening these cellular barriers.
 
Notably, these results also align with previous research indicating that PrEP does not significantly alter the cellular environment of the foreskin. Previous studies involving mucosal tissues, including cervical and vaginal areas, reported comparable results, suggesting that PrEP’s protective effect against HIV does not involve altering TJ integrity.
 
Future Directions in PrEP Research
Although this study provides compelling evidence for the safety of PrEP in terms of TJ expression in foreskin tissue, it raises further questions about how long-term use might impact other cellular functions or tissues. Given that PrEP is increasingly used worldwide, including among high-risk populations, understanding any cumulative effects on tissue structure and immune response is essential.
 
Moreover, exploring gene expression at the single-cell level in foreskin tissue could offer even deeper insights into how specific cell types, like Langerhans cells (HIV target cells in the foreskin), interact with PrEP. Such studies could reveal additional layers of PrEP’s safety profile and potentially lead to even more effective HIV prevention strategies.
 
Conclusion
In summary, the CHAPS trial findings support that PrEP, whether in single or double doses, does not alter the critical TJ gene expression in foreskin tissue. This reaffirms PrEP as a safe preventive option against HIV, with no compromising effects on cellular barriers that could increase vulnerability to viral infections. As PrEP usage continues to expand globally, these findings bolster confidence in its long-term application, contributing to safer and more effective HIV prevention approaches.
 
The study findings were published in the peer-reviewed journal: Frontiers in Immunology.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1415475/full
 
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