Imagine a forest fire. Flames jump from tree to tree, leaving destruction in their wake. Only the trees burn, but the fire wreaks havoc on the entire ecosystem. Birds have nowhere to build nests; the soil can no longer absorb water. Human immunodeficiency virus (HIV) is like a fire to the immune system. The virus infects and kills CD4+ T cells, which play a crucial role in coordinating the functions of other immune cells. In people living with HIV, the cumulative infection and death of CD4+ T cells leads to immune system dysfunction and increased susceptibility to infections and cancers.
Existing treatment for HIV, called antiretroviral therapy (ART), is like a flame retardant that can protect new trees from catching fire but does not put out already-burning trees. With this flame retardant, most trees burn out and do not present ongoing danger. However, some trees retain long-lasting embers. Under the right conditions, the embers reignite and new trees, if not protected by the flame retardant, catch fire and further spread the flames. In people living with HIV, ART prevents infection of new CD4+ T cells but does not eliminate already-infected cells. So-called latently infected cells persist for decades and maintain the potential to reactivate infection if ART is stopped, a phenomenon known as viral rebound. People living with HIV must take lifelong ART to prevent viral rebound and immune system damage.
The Cohn lab in the Vaccine and Infectious Disease Division studies latently infected cells and their interactions with other parts of the immune system to identify potential strategies for an HIV cure. In a recent study published in The Journal of Infectious Diseases, the group sought to characterize the immune response to rebounding HIV in people who stop taking ART. “We don’t understand how the immune system responds to this pathogen that it’s seen fairly frequently at very low levels for perhaps decades but hasn’t had to directly tackle in a very long time,” said Anna Farrell-Sherman, a graduate student in the Cohn lab and lead researcher on the study. In this unique immune circumstance, what parts of the immune system detect viral rebound? How do they respond?
To answer these questions, the team characterized immune function in people living with HIV while undergoing an analytical treatment interruption. Participants took a short pause in ART treatment while under close observation by clinicians. All participants experienced brief HIV rebound before resuming ART. The research team analyzed participant blood samples from throughout the process – before stopping ART, during ART interruption, and after detectable rebound. They measured the expression of RNA and proteins across many immune cell types to determine changes in immune activity.
The study team found that in all 10 participants evaluated, a type of immune cell called CD16+ monocytes increased in abundance before viral rebound was detectable by the standard clinical test. Monocytes are innate immune cells, meaning they recognize and attack pathogens in general rather than learning to target a specific microbe. They play a crucial role in killing invading pathogens and communicating with other immune cells about the infection. CD16+ monocytes, also known as non-classical monocytes, specialize in surveillance of pathogens and production of antiviral signals. The increase of CD16+ monocytes early in HIV rebound may speed up viral detection throughout the body and amplify the signals alerting other immune cells to the virus.
The study found that in addition to increasing in abundance, CD16+ monocytes also increased their expression of genes promoting inflammation and antiviral activity. This suggests that CD16+ monocytes detect and work to suppress emerging rebound virus before it becomes detectable to clinicians. They are the first responders to the reigniting forest fire – they smell the smoke and pull out their hoses before anyone else sees a flame.
Finding that CD16+ monocytes are the first immune cells to respond to HIV viral rebound is significant for the field of HIV immunology. “Monocytes in general are not well studied in the context of HIV and AIDs,” commented Farrell-Sherman. “The results tell us we need to be looking more closely at what’s going on here.”
Moving forward, the Cohn lab is interested in determining whether CD16+ monocytes contribute to immune control of latently infected cells. In some rare individuals living with HIV, the immune system can suppress HIV to low levels without treatment. Farrell-Sherman shared, “we know that some people can live without taking ART and control their own virus, and if we can figure out how and why, we can help more people do that.”
The spotlighted research was funded by the National Institute of Allergy and Infectious Disease and the Bill and Melinda Gates Foundation.
Farrell-Sherman A, de la Force N, Prator CA, Valieris R, Azam W, Da Silva I, Deeks SG, Thanh C, Bosch RJ, Henrich TJ, Cohn LB. 2025. Antiviral Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia. The Journal of Infectious Diseases. doi: 10.1093/infdis/jiaf367
Source : Fred Hutchinson Cancer Center
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