A University of Maryland, Baltimore County (UMBC) scientist has received a two-year grant from the National Institute of Allergy and Infectious Diseases (NIAID) to explore how two key HIV prevention drugs work inside the body—specifically in colon tissue, where HIV transmission risk is especially high. The project, led by Herana Kamal Seneviratne, assistant professor of chemistry and biochemistry, seeks to explain why these drugs protect some people better than others and could help make prevention tools more reliable.

HIV continues to pose a major global health challenge, with about 1.3 million new infections reported annually worldwide in recent years. One of the most important prevention strategies is pre-exposure prophylaxis, or PrEP. Healthy individuals at risk of HIV take a daily pill containing two antiretroviral drugs—tenofovir (TFV) and emtricitabine (FTC)—to block the virus before it can take hold.

These drugs only become protective after they are modified inside cells, specifically by adding a phosphate group in a step called “phosphorylation.” This activation turns them into their working forms. However, people’s responses to the drugs vary widely, sometimes leading to reduced protection.

“One of the reasons for PrEP failure is the huge variability observed among individuals,” Seneviratne explains. This variability is concerning, because someone might partake in riskier behavior based on a belief that they are safer than they actually are.

Seneviratne’s work focuses on the colon, because unprotected anal sex carries an 18-fold higher risk of HIV transmission than vaginal sex. Oral PrEP spreads through the bloodstream, but the amount of active drug that reaches colon tissue is not well studied, and could be one of the reasons for variable drug responses. Understanding what happens in these tissues is therefore crucial for improving PrEP, Seneviratne says, particularly for men who have sex with men.

Mapping cellular machinery

Previous work, including from Seneviratne’s group, has shown that certain enzymes are involved in activating and deactivating PrEP drugs in the blood by adding and removing phosphate groups. Certain kinases add a phosphate group, and certain nucleotidases remove it. However, the activity of these enzymes in colon tissue is unknown. 

“What matters is the drug metabolite concentrations in specific sites like in colon. That’s the point that we’re trying to make,” Seneviratne says.

To address that knowledge gap, Seneviratne’s team will grow human colon cells in the lab and use genetic tools to modify the expression of these kinases and nucleotidases one at a time. Then they will measure how those changes affect the drugs’ phosphorylation status. The project will take an innovative approach using mass spectrometry imaging, a technique that lets researchers see where molecules are located and active inside tissues.

“Our group is trying to contribute to overall improved HIV prevention,” Seneviratnes says. To that end, “understanding the metabolism of these two drugs in colon tissue is important.”

In conjunction with the lab’s work with human cells, Seneviratne’s team will examine mouse colon tissue to map these enzymes’ presence and activity across different cell types and tissue regions. The project will combine traditional techniques—specifically enzyme histochemistry and mass spectrometry—in novel ways. The dual approach will allow the team to observe enzymatic activity directly in its natural tissue environment rather than in a test tube, Seneviratne explains.

The NIAID grant type supporting the work, an R21, supports innovative high-risk, high-reward ideas that push scientific boundaries. Work is already underway on this approximately $440,000, two-year award. Graduate students Korin Murray and Nimalee Jayasekera and research fellow Christian Oh will take leading roles. Jayasekera will focus on the cell and molecular biology aspects, Murray will work on advanced imaging and tissue analysis, and Oh will support both students. There will be opportunities for undergraduates as well. Overall, the project expands the group’s focus on the negative side effects of drugs that treat HIV (including a study led by chemistry Ph.D. student Nav Raj Phulara on the brain) into the effectiveness of HIV prevention drugs.

From the bench to better PrEP

By revealing how these enzymes control drug activation and deactivation in specific parts of the colon, the project aims to provide knowledge that could lead to better dosing strategies, improved formulations, or other ways to make PrEP more effective. “The data that we generate from this work, we can leverage to optimize the therapeutic efficacy of the HIV PrEP drugs,” Seneviratne said. “These two drugs set the foundation for HIV prevention.”

Seneviratne’s interest in this area grew from his postdoctoral training at Johns Hopkins University, where he worked closely with clinicians to identify pressing real-world problems, leading him to ask, “How can I use my bioanalytical chemistry expertise to address those questions?” His chemistry expertise, combined with early publications on these enzymes, provided the foundation for the proposal.

This kind of fundamental research strengthens public health tools like PrEP, helping more people stay protected against HIV. The findings could eventually support more personalized or reliable prevention approaches across diverse populations.

PrEP, the cornerstone of contemporary HIV prevention, involves the administration of antiretroviral drugs to individuals at high risk of infection, drastically reducing their likelihood of contracting the virus. While this strategy has been transformative, variability in its protective efficacy across different populations and adherence levels has sparked a quest to elucidate precise biological markers that predict and measure its protective potency. The recent study addresses this critical gap by focusing on pharmacological markers that reflect drug activity and distribution within the key anatomical sites implicated in sexual transmission.

At the core of the study lies an intricate examination of pharmacokinetics and pharmacodynamics of PrEP medications—principally tenofovir and emtricitabine—the agents most prevalently employed in oral formulations. The investigative spotlight turns to the mucosal tissues lining the rectum and the plasma concentration levels, domains crucial to understanding how the drugs permeate and hold activity where HIV transmission predominantly occurs in MSM. Through rigorous clinical sampling and analytical methodologies, the team charted drug concentrations and correlated them with viral suppression probabilities.

What differentiates this research is its nuanced approach to dissecting the pharmacological milieu within the targeted tissues rather than relying solely on systemic plasma levels. Plasma concentrations, while informative, do not always accurately mirror the drug availability at mucosal portals of entry, which are the initial battlegrounds for viral infection. By quantifying the intracellular metabolites of the drugs in rectal tissue biopsies, the study identifies a more reliable set of pharmacological markers predictive of protective efficacy, offering a window into the actual biological defense mounted by PrEP in vivo.

The implications of this refined pharmacological profiling are profound. By aligning therapeutic monitoring with these markers, healthcare providers can tailor priors on PrEP effectiveness, optimize dosing regimens, and perhaps even reduce unnecessary drug exposure. This precision in prevention is vital as it balances efficacy with tolerability and cost, enhancing adherence by minimizing side effects and ensuring sustainable long-term use, ultimately contributing to curbing HIV incidence.

Furthermore, the study’s extensive analysis elucidates significant interindividual variability in drug absorption and tissue penetration, influenced by genetic, metabolic, and possibly behavioral factors. Such variability underscores the necessity of personalized medicine frameworks in HIV prevention, moving beyond one-size-fits-all regimens. The identified pharmacological benchmarks could serve as a foundation to stratify patients based on their tissue drug concentrations, enabling clinicians to intervene preemptively with adherence support or alternative dosing strategies.

Intriguingly, the research also opens avenues to explore how these pharmacological markers interact with other biological elements such as immune responses in mucosal tissues. Understanding whether higher drug concentrations correlate with enhanced local immune activation or suppression may provide insights into comprehensive biological defenses against HIV acquisition, adding layers of complexity—and potential innovation—to prevention science.

The methodology leveraged cutting-edge liquid chromatography-tandem mass spectrometry, coupled with innovative tissue sampling technologies, to capture a robust dataset reflective of real-world scenarios. Participants from diverse MSM cohorts contributed to the representativeness of the findings, bolstering the translational potential of the markers identified. These technical underpinnings ensure that the study’s conclusions rest on a solid empirical foundation that will inspire confidence in the broader application of these pharmacological markers.

Beyond the immediate clinical implications, the study also emphasizes the need for continued surveillance and dynamism in HIV prevention strategies as viral epidemiology and behavioral patterns evolve. The pharmacological markers provide a quantifiable metric to adaptively manage PrEP delivery, potentially enabling more responsive public health interventions tailored to shifting risk landscapes within MSM communities.

Moreover, this research paves the way for exploring similar pharmacological paradigms in other high-risk groups, including heterosexual populations and intravenous drug users, broadening the impact of these findings beyond the initial MSM focus. Understanding whether analogous tissue drug concentrations confer comparable protection could harmonize prevention efforts across diverse epidemiological contexts.

As oral PrEP moves into its third decade of clinical use, innovations such as these pharmacological markers underscore the evolution from empirical to precision HIV prevention. This transition aligns with broader trends in medicine, where biomarker-driven decisions are revolutionizing patient care, risk stratification, and therapeutic monitoring, thereby optimizing outcomes while curtailing costs.

The study also highlights challenges ahead, including standardizing tissue sampling across clinical settings and translating these markers into accessible assays for routine use. Addressing these hurdles will demand coordinated efforts spanning researchers, clinicians, and public health stakeholders committed to harnessing the full power of pharmacological insights.

In conclusion, the elucidation of pharmacological markers for HIV prevention among MSM marks a seminal achievement in optimizing oral PrEP. By furnishing a molecular blueprint that aligns drug presence within critical mucosal environments with protective efficacy, the study charts a path toward personalized, adaptable, and more effective HIV preventive care. As the global community strives toward the ambitious goal of ending the HIV epidemic, such innovations are indispensable milestones steering us closer toward a world free from HIV transmission.

Subject of Research: Pharmacological markers associated with oral pre-exposure prophylaxis efficacy for HIV prevention in men who have sex with men.

Article Title: Pharmacological markers of HIV prevention for oral pre-exposure prophylaxis in men who have sex with men.

Article References:
Iannuzzi, S., Müller, M., Yu, Y. et al. Pharmacological markers of HIV prevention for oral pre-exposure prophylaxis in men who have sex with men. Nat Commun 17, 4213 (2026). https://doi.org/10.1038/s41467-026-72907-6

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41467-026-72907-6