E. Shyam P. Reddy: A new method to genetically tag immune cells that carry HIV by the Icahn School of Medicine
Shyam P. Reddy, Professor and Director of the Cancer Biology Program, Department 0f OB/GYN at Morehouse School of Medicine, shared a post on LinkedIn:
“Researchers from the Icahn School of Medicine at Mount Sinai have developed a new method to genetically tag immune cells that carry HIV, allowing them to study the reservoir of immune cells where the virus hides.
The study, published in Nature Communications, represents a step forward in the development of curative therapies for HIV, which affects nearly 40 million people globally.
Antiretroviral therapies are effective at halting the spread of HIV, but they cannot cure the disease, which is largely due to the fact that the virus is able to hide within immune cells in a latent state. While latent HIV is known to mainly reside in CD4 T cells, there are yet no certain markers of the HIV reservoir, making it difficult to identify, study, and target the dormant virus with therapeutic agents.
“If we can identify the cells infected with HIV, it will help bring us closer to figuring out how to eliminate them,” said Benjamin K. Chen, professor of medicine (infectious diseases), microbiology, pharmacological sciences, and immunology and immunotherapy at the Icahn School of Medicine at Mount Sinai.
“This is a new model that enables us to identify cells that harbor dormant HIV and give an unbiased picture of what the cells look like and what kind of T cells are more likely to survive after being infected with HIV.”
Chen’s team developed a genetic tracing system, which they called the HIV-1-induced lineage tracing (HILT) system, and used it to introduce a genetic switch into CD4 T cells. The switch is designed to activate when the cell is infected by HIV, turning from red to green, and remains active even when the virus becomes dormant, permanently marking the immune cells where the HIV reservoir hides.
“We use human blood stem cells, and genetically modify them with a genetic switch that flips on—irreversibly—when a cell gets infected with HIV,” said Chen. “When introduced into a mouse that lacks an immune system, it grows an entire human immune system that can sense when cells become infected with a variant of HIV.”
Using single-cell RNA sequencing, the researchers profiled over 47,000 T cells from eight humanized mice generated using the HILT system. This allowed them to identify nine distinct types of T cells that contained latent HIV.
A comparative analysis of marked cells during active HIV infection and after undergoing antiretroviral treatment showed common genetic pathways being modulated in opposite directions across all types of T cells. These included the EIF2, Sirtuin, and protein ubiquitination pathways.
“The results provide an early picture of what latent cells look like,” said Chen. “We see that while there are many different types of T cells that harbor HIV, they do generally express some common gene pathways that may promote their survival or allow the virus to remain dormant.”
These genetic profiles, he added, are a promising target for future gene therapies to awaken and eliminate dormant HIV. Eventually, this gene therapy …”
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