Tumor-Like Tissue Environments Could Hold Clues to Curing HIV

Viral reservoirs in a proxy animal model of HIV share features with immune-suppressive tumors

The tissue microenvironments surrounding HIV-infected immune cells look a lot like those surrounding cancerous tumors, reports a new Northwestern University study published in the journal Frontiers in Immunology.

The findings help explain why HIV has been so difficult to cure. Scientists found that viral reservoirs exist within tissue microenvironments that resemble immune-suppressive tumor microenvironments, suggesting that future HIV cure strategies may benefit from approaches traditionally used in cancer therapy.

By integrating molecular imaging, spatial transcriptomics and machine learning, the scientists created a detailed map of the viral microenvironment in animal models with Simian Immunodeficiency Virus (SIV), which is commonly studied to better understand HIV. In doing so, they identified shared biological programs between viral persistence and tumor 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, PhD, assistant professor of Medicine in the Division of Infectious Diseases. “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.”

Viral reservoirs create a ‘sanctuary’ for HIV to thrive

The resemblance to cancer emerged from the scientists’ effort to better understand viral reservoirs, the small pockets of virus that remain hidden in the body after treatment. These can reignite infection if therapy is stopped, making a functional cure difficult to achieve.

“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.”

Study zooms out to see the entire HIV microenvironment

To understand why these reservoirs persist for decades, the investigators looked beyond the infected cells themselves.

Previous studies focused on identifying the cells that harbor HIV. This study instead examined the broader tissue microenvironment, revealing how the surrounding “neighborhood” 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 neighborhood — 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 neighborhood so the immune system can move in, break down these reservoirs and finally do its job.”

The findings lay critical groundwork for future HIV cure strategies aimed not only at eliminating infected cells, but also at disrupting the environments that protect them and make viral persistence possible.

Studying gut tissues — not just blood — revealed tumor environment similarities

The tumor-like characteristics became apparent only when the scientists examined SIV reservoirs within gut tissue, where most persistent virus survives during therapy. This was novel compared to previous research that focused only on blood samples.

Two Northwestern labs approached the problem in complementary ways, allowing them to see the same phenomenon from multiple perspectives. Co-corresponding author Thomas J. Hope, PhD, professor of Cell and Developmental Biology and of Obstetrics and Gynecology, likened the collaboration to reconstructing events at a party. His lab’s imaging methods provided snapshots of what is happening in 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 Ramon 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 labs, located and analyzed rare sites of viral persistence within tissues in the guts of non-human primate animal models.

The team noticed the collection of cells, signals and tissues that surround viral reservoirs, called the viral microenvironment (VME), may share important features with so-called “cold” tumor microenvironments (TME), which are known to suppress immune responses and resist clearance by the body’s defenses.

“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.”

The reservoirs that shared features with the “cold” tumors showed increased activity in biological pathways linked to tissue remodeling and immune suppression. In contrast, short-lived reservoirs more closely resembled “hot” tumors, 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 around viral reservoirs.

Using machine learning, the team identified several human genes, including KRT8, EPCAM and RRM2, as important contributors to the tumor-like features seen in persistent viral reservoirs.

Together, the findings suggest HIV persistence depends not only on infected cells, but also on the tissue environments that shield them. By disrupting those protective environments, investigators may eventually make viral reservoirs more vulnerable to immune attack, much as cancer therapies seek to overcome immune-suppressive tumor microenvironments.

Natalie Stegman, a student in the Driskill Graduate Program in Life Sciences (DGP), was co-author on the study.

Funding for the study was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grants P01AI169600, R01MH125778, RL-R; R37AI094595, 1U54AI170856-01, R01AI177265, P01AI131346 and P30 AI117943).

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