How HIV Infection "Exhausts" the Immune System

Research Aims to Kick Start Defensive Immunity in People with HIV

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Photograpy © International AIDS Vaccine Initiative (IAVI)

HIV has the unique ability to evade detection by inserting its genetic material into hidden cells and tissues of the body, known as latent reservoirs. Rather than destroying these cells, the latent HIV silently replicates from generation to generation within the host cell, wholly invisible to the immune system.

Research has long been focused on ways to  release HIV from these hidden reservoirs and to stimulate the body's response so that it can effectively eradicate the virus once and for all.

While the strategy, known as "kick-kill" (also referred to as "shock-kill"), has made advances in the way of HIV activation, it has fallen well short in the neutralization of these newly released virus.

Part of the problem is that the immune system continually monitors itself in order to ensure that it neither overactivates nor underactivates when faced with an invading pathogen. Overactivation occurs when the body's immune system literally turns against itself, as can happen with autoimmune diseases like lupus, multiple sclerosis and celiac disease. Underactivation, by contrast, occurs when the body fails to recognize when a normal biological process suddenly becomes pathogenic (one of the theories into the development of cancers).

By continually keeping itself in the check, the immune systems can sometimes inadvertently "put the brakes" on an appropriate response to a chronic infection like HIV.

The phenomenon, aptly referred to as "exhaustion," occurs when molecular receptors on the surface of cells called immune checkpoints (ICs) tamper the immune response over time, making the body less and less able to mount a robust defense.

Disabling Immune Checkpoints to Fully Activate Immune Response

A number of research teams have begun to explore ways of blocking ICs so that the immune function can effectively revived in chronically infected people with HIV.

One such team, led by Dr. Mirko Paiardini of Emory University, was able to identify an IC predominant in host cells latently infected with HIV called CTLA-4.

The researchers suggested that an immunotherapeutic approach—using a monoclonal (single cloned) antibody called ipilimumab—may be able to block CTLA-4 expression and stimulate the activation of T-cells central to body's immune defense. (Ipilimumab is currently approved for use in the treatment of late-stage melanoma.)

Another team, led by Dr. Glen Chew of the University of Hawaii, was able to improve the activation of HIV  killer T-cells by blocking two separate ICs—called TIGIT and PD-L1—again with IC-specific monoclonal antibodies.

Both studies suggest that passive immunization using key IC-specific monoclonal antibodies may revive the immune function of people chronically infected with HIV and pave the way to the development novel "kick-kill" strategies—either on its own or in conjunction with standard antiretroviral therapy.

The research may also lead to biomedical interventions for other chronic viral infections such as hepatitis C, in which infected individuals can experience terminal immune exhaustion, typically with the same triggers that tamper immune response in people with HIV.


amfAR, the Foundation for AIDS Research. "Release the Brakes to Make HIV Go." New York, New York; published online August 18, 2015.

McGary, C. "CTLA-4-expressing CD4 T cells are critical contributors to SIV viral persistence." International AIDS Society Conference 2015; Vancouver, Canada; July 19-22, 2015; poster presentation; abstract WEPEA143.

U.S. Food and Drug Administration (FDA). "FDA approves new treatment for a type of late-stage skin cancer." Silver Spring, Maryland; press release issued March 25, 2011.

Chew, G.; Fujita, T.; Clayton, N.; et al. "Investigating the role of the immune checkpoint receptor TIGIT in T cells during HIV disease progression and as a target for immune restoration." International AIDS Society Conference 2015; Vancouver, Canada; July 19-22, 2015; oral abstract OA3-5 LB. Tetro,

J. "The Path to Immune Burnout: Researchers Have Found a Cell Marker That May Lead to Terminal Exhaustion." Popular Science; published October 27, 2015. 

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