Researchers from the University of Illinois have demonstrated the importance of cell-type-specific targeting in the treatment of HIV. Their study, published in the Proceedings of the National Academy of Sciences, is one of the first to examine the differential or cell-type specific effects of HIV latency modulation on myeloid cells, a type of immune cell made in bone marrow.

A major barrier to eliminating HIV infection is how to manage latency, or the period in which an infected cell is dormant and unable to produce virus. Latent HIV cells congregate throughout the body in pockets known as reservoirs. Latent reservoirs are problematic because they can start producing virus at any time.

Complete eradication of the disease would require removal of all latent cells from the body or permanent resistance to activation stimuli. But reactivation can be triggered by numerous factors, including cues that direct the differentiation of myeloid cells.

For years, HIV cure research has centered around two approaches, known as "shock and kill" and "block and lock." The former works in tandem with antiretroviral therapy to activate latently infected cells and deplete them through apoptosis, or programmed cell death, while the latter forces infected cells into a deep latent state from which they cannot spontaneously reactivate.

Research around these techniques has historically focused on a type of white blood cell called a T-cell, which is the main target of HIV infection. But latent reservoirs are composed of more than just T-cells; in fact, they contain dozens of diverse cell types, each with their own unique HIV gene expression patterns.

"There is a huge amount of heterogeneity in cells, even within the same lineage," said Collin Kieffer, an assistant professor of microbiology and an author on the paper. "The variability of response within these reservoirs increases with each new cell type."

Alexandra Blanco, a Ph.D. student in Kieffer's lab, wanted to study cell types that had been overlooked in conventional HIV research. Concentrating on myeloid cells, she created a clonal library containing 70 populations of latently infected monocytes. Blanco then analyzed the clonal populations and their responses to activation. The responses varied significantly, highlighting a large degree of heterogeneity within a single cell type.

This observation prompted a new question: Do different cell types exhibit different responses to HIV latency treatment? Indeed, their study results showed that certain HIV latency therapeutics can promote latency in T-cells and monocytes, while reversing latency in macrophages.

"Not all cells in the body are the same," Kieffer said. "So it makes sense that not all HIV-infected cells would react to the virus in the same way."

Their paper highlights the need for future HIV treatments to consider all types of cells and the ways each cell might respond to potential therapies.

Their findings build upon the research of Roy Dar, a former Illinois professor of bioengineering whose lab studied heterogeneity in HIV gene expression.

"He started this, and we picked it up and moved it to its current state," Kieffer said. "So collaboration really built the foundation for these results. It's evolved into a new direction for our lab, and one we're really excited about."

An additional and unexpected finding from Blanco's analysis revealed changes to cell size and shape in response to infection, suggesting that HIV can alter cell morphology. Blanco's next goal is to identify the biological mechanisms behind these phenotypic changes.

Kieffer and members of his lab also look forward to reproducing their results—which were mostly conducted on a cell line—in primary cells. Replicating the results in a more human-like model would enhance the study's clinical relevancy, Kieffer explained.

"We'd like to conduct larger screens in T-cells, monocytes, and macrophages to identify potential drugs that could work across all these cell types," Blanco said. "We might be able to find even more molecules that don't behave in a cell-type-specific manner."

More information: Alexandra Blanco et al, Monocyte to macrophage differentiation and changes in cellular redox homeostasis promote cell type-specific HIV latency reactivation, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2313823121