Researchers at the University of Hawaiʻi and Oregon Health Sciences University have revealed a novel new immune pathway that can be targeted to increase the immune systems’ ability to eliminate HIV, the virus that can lead to AIDS.
The research team led by Lishomwa Ndhlovu at the John A. Burns School of Medicine (JABSOM) Hawaiʻi Center for AIDS, and Jonah Sacha, from OSHU, identified a novel negative checkpoint receptor on T cells, TIGIT, which may be responsible for making immune cells dysfunctional and unable to control or eliminate the HIV virus.
The discovery, published in the January 2016 issue of the scientific journal PLoS Pathogens, will give new directions to vaccines and therapies that will potentially reverse these exhausted cells and allow them to control HIV-1 replication, but also serve in “Shock and Kill” HIV curative strategies.
When a person becomes infected with HIV, starting combination antiretroviral drug treatment will, in most cases, successfully suppress HIV in the blood. However, the treatment is powerless to clear infection and restore full health. Furthermore, if people with HIV stop taking antiretroviral drugs, they experience a rapid, aggressive rebound of the virus in the blood. This indicates that HIV has found a way to hide and establish a “dormant reservoir”, but more importantly, evade elimination by the immune system.
In the absence of treatment, HIV infection is brought partially under control by the infected person’s immune system, specifically by an immune system cell called a CD8+ Killer T cell. The response of these CD8+ T cells and HIV during the early stages of infection is crucial and will determine how the disease will progress. Over time, however, the immune damage mediated by HIV infection will affect the function of the CD8+ T cells even if with the addition of antiretroviral drugs.
These immune cells are key players in eliminating HIV infected reservoir cells. One proposed strategy to eradicate HIV being considered is the ‘Shock and Kill’ approach, first to ‘Shock’ the infected cells with agents that will awaken the dormant virus and then allow the immune system to ‘Kill’ the reactivated virus. A major obstacle with this approach has been that although CD8+ Killer T cells can recognize HIV-1 infected cells, these T cells are unable to eliminate the reactivated HIV viral reservoir.
“A preponderance of emerging evidence indicates that the functions of the HIV-specific CD8+ Killer T cells are severely compromised and enters a state of ‘exhaustion,’ rendering the cells less effective at eliminating HIV infected cells” said Glen Chew, a PhD candidate in immunology at JABSOM and lead author of the study.
Discovering a pathway to clearing HIV infection
The researchers observed an expansion of CD8+ T cells expressing, a negative immune checkpoint receptor, TIGIT was associated with clinical markers of HIV disease progression in a diverse group of HIV infected persons. These levels remained high even among those with undetectable virus in the blood. They also found the large fraction of the HIV-specific CD8+ T cells simultaneously express both TIGIT and another negative checkpoint receptor, PD-1 and these cells retained several features of exhausted T cells.
Evaluating Simian Immunodeficiency Virus (SIV) infection of the rhesus macaque non-human primate, has served as an indispensible animal model for studying HIV/AIDS. The authors next defined the TIGIT pathway in this model. “We were successful in cloning rhesus TIGIT and were able to demonstrate, similar to humans, that the TIGIT pathway was active in SIV infection.” said co-author Gabriella Webb, a postdoctoral researcher in the Sacha Lab.
“These results appear to indicate that a large fraction of HIV and SIV specific CD8+ T cells are vulnerable to negative regulation through these two pathways” said Ndhlovu, an associate professor at UH’s Department of Tropical Medicine and Hawaiʻi Center for AIDS.
The research team reasoned that by interfering with the TIGIT and PD-1 pathway, they could rejuvenate the HIV-specific CD8+ T cell responses to clear HIV infection. By blocking both the TIGIT and PD-1 pathways with novel targeted monoclonal antibodies, the researchers were able to reverse the defects of these viral specific CD8+ T cells.
Read the John A. Burns School of Medicine news story for more information.