46 The tissue microenvironments surrounding HIV-infected immune cells closely resemble those found around cancerous tumours, according to a new Northwestern University study. The findings may help explain why HIV has proved so difficult to cure. Researchers found that viral reservoirs, small pockets of virus that remain hidden in the body after treatment and can restart infection if therapy is stopped, exist within tissue microenvironments resembling those found in immune-suppressive tumours. This suggests that future HIV cure strategies could benefit from approaches traditionally used in cancer treatment. The study was published on 4th August in the journal Frontiers in Immunology. By integrating molecular imaging, spatial transcriptomics, and machine learning, the scientists created a detailed map of the viral microenvironment in animal models infected with Simian Immunodeficiency Virus (SIV), which is commonly studied to better understand HIV. They identified shared biological processes involved in viral persistence and tumour immune evasion. “We are interested in the similarities with cancer because to cure any type of cancer, you need to deal with a series of factors, not just one thing,” said corresponding author Ramon Lorenzo-Redondo, assistant professor of medicine in the Division of Infectious Diseases at Northwestern University Feinberg School of Medicine. “We are now trying to understand the chain of events that leads to that environment to then target all the components of this multi-component, multi-systemic problem.” “We think the virus promotes a whole sanctuary-type environment that allows it to survive, but also, because it’s immune exclusive, it stops the cells that are supposed to kill the virus,” Lorenzo-Redondo said. “As soon as you remove treatment, because these populations are ready to go and cannot be cleared, they again trigger a chain of events that will infect other cells.” To understand why these reservoirs persist for decades, the researchers looked beyond the infected cells themselves. Previous studies have focused on identifying the cells that harbour HIV. This study instead examined the broader tissue microenvironment, revealing how the surrounding environment helps the virus persist and rebound when treatment stops. “Imagine the infected cell is a beautiful house, set near the beach with a stunning mountain view,” Lorenzo-Redondo said. “If you change the neighbourhood — build a highway through it, remove what makes it desirable — you make it much harder for anyone to stay. Our goal is to understand how to reshape that neighbourhood so the immune system can move in, break down these reservoirs, and finally do its job.” The findings provide important groundwork for future HIV cure strategies aimed not only at eliminating infected cells, but also at disrupting the environments that protect them and enable viral persistence. The tumour-like characteristics became apparent only when the scientists examined SIV reservoirs in gut tissue, where much of the persistent virus remains during treatment. This was a significant departure from previous research, which focused primarily on blood samples. Two Northwestern laboratories approached the problem in complementary ways, allowing the researchers to observe the same phenomenon from multiple perspectives. Co-corresponding author Thomas J. Hope, professor of cell and developmental biology and obstetrics and gynaecology at Feinberg, compared the collaboration to reconstructing events at a party. His laboratory’s imaging methods provided snapshots of what was happening in the tissues at a given moment, while Lorenzo-Redondo’s computational analyses revealed the relationships and interactions occurring behind the scenes. “With imaging, we’re taking snapshots of the party,” Hope said. “We can see who’s there, where they are and what’s happening in that moment. But orenzo-Redondo can use these large-scale sequencing datasets to figure out who was talking to whom, what groups formed and how the interactions changed over time.” Using a novel imaging and spatial transcriptomics platform that combines immunoPET/CT-guided tissue mapping with high-resolution genomic analysis, the scientists, led by Eliana Crentsil, a graduate student in Hope’s and Lorenzo-Redondo’s laboratories, located and analysed rare sites of viral persistence in the gut tissues of non-human primate models. The team found that the collection of cells, signals, and tissues surrounding viral reservoirs, known as the viral microenvironment, may share important features with so-called “cold” tumour microenvironments. These environments are known to suppress immune responses and resist clearance by the body’s defences. “When two completely different approaches keep pointing to the same conclusion, it gives you a lot of confidence that you’ve uncovered something real,” Hope said. “In our case, both approaches pointed to HIV reservoirs existing within tissue environments that resemble those seen in difficult-to-treat cancers.” Reservoirs that shared features with “cold” tumours showed increased activity in biological pathways linked to tissue remodelling and immune suppression. By contrast, short-lived reservoirs more closely resembled “hot” tumours, which attract stronger immune responses, and showed higher levels of immune cells capable of killing infected cells. The scientists also found that regulatory T cells, which help control immune activity, played a central role in the cell-to-cell communication networks surrounding viral reservoirs. Using machine learning, the team identified several human genes, including KRT8, EPCAM, and RRM2, as important contributors to the tumour-like features observed in persistent viral reservoirs. Together, the findings suggest that HIV persistence depends not only on infected cells, but also on the tissue environments that protect them. Disrupting these protective environments could eventually make viral reservoirs more vulnerable to immune attack, much as cancer therapies seek to overcome immune-suppressive tumour microenvironments. The study, titled “A tissue microenvironment analogous to certain tumour microenvironments facilitates HIV persistence”, was co-authored by Northwestern’s Natalie Stegman.