'Pep talk' can revive immune cells exhausted by chronic viral infection

December 13, 2011

Chronic infections by viruses such as HIV or hepatitis C eventually take hold because they wear the immune system out, a phenomenon immunologists describe as exhaustion.

Yet exhausted immune cells can be revived after the introduction of fresh cells that act like coaches giving a pep talk, researchers at Emory Vaccine Center have found. Their findings provide support for an emerging strategy for treating chronic infections: infusing immune cells back into patients after a period of conditioning.

The results are published this week in Proceedings of the National Academy of Sciences Early Edition.

The first author of the paper is Rachael Aubert, a student in Emory's Immunology and Molecular Pathogenesis program who completed her doctorate in 2009. Senior author Rafi Ahmed, PhD, is director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

Ahmed's laboratory has extensive experience studying mice infected with lymphocytic choriomeningitis virus (LCMV). Immune responses against LCMV are driven by CD8 or "killer" T cells, which destroy virus-infected cells in the body. But a few weeks after exposure to LCMV, the mice develop a chronic infection that their immune systems cannot shake off, similar to when humans are infected by viruses like HIV and hepatitis C.

Aubert and her co-workers examined what happened to mice chronically infected with LCMV when they infused CD4 or "helper" T cells from uninfected mice. After the infusion, the CD8 cells in the infected mice revived and the levels of virus in their bodies decreased by a factor of four after a month. Like coaches encouraging a tired athlete, the helper cells drove the killer cells that were already in the infected mice to emerge from exhaustion and re-engage.

The cell-based treatment was especially effective when combined with an antibody that blocks the molecule PD-1, which appears on exhausted T cells and inhibits their functioning. The antibody against PD-1 helps the exhausted T cells to revive, and enhances the function of the helper cells as well: the combination reduced viral levels by roughly ten-fold, and made the virus undetectable in some mice.

"We have not seen this sharp of a reduction in viral levels in this system before," says co-author Alice Kamphorst, a postdoctoral fellow.

The helper cells were all genetically engineered to recognize LCMV, a difference between mouse experiments and potential clinical application. However, it may be possible to remove helper T cells from a human patient and stimulate them so that all the cells that recognize a given virus grow, Kamphorst says.

"This is an active area of research and several laboratories are looking at how best to stimulate T cells and re-introduce them," she says.

In addition, she and her co-workers are examining what types of hormones or signaling molecules the helper cells provide the killer cells. That way, that molecule could be provided directly, instead of cell therapy, she says.

The molecule PD-1 was previously identified by Ahmed and colleagues as a target for therapy designed to re-activate exhausted immune cells. Antibodies against PD-1 have been undergoing tests in clinical studies against hepatitis C and several forms of cancer.
-end-
Collaborators from Harvard Medical School/Dana Farber Cancer Institute contributed to the paper. The research was supported by the National Institutes of Health and the Cancer Research Institute.

Reference: R.D. Aubert et al. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. PNAS Early Edition (2011).

Emory Health Sciences

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.