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UH scientists discover a cellular pathway that may re-energize immune cells to eliminate HIV

Date: January 9th, 2016 in JABSOM News, Research    Print or PDF

Glen Chew speaking at the conference.

Researchers at the University of Hawai’i (UH) and Oregon Health Sciences University (OHSU) 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, MD, PhD, at the UH John A. Burns School of Medicine (JABSOM) Hawaiʻi Center for AIDS, and Jonah Sacha, PhD, 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.

Background
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 UH-JABSOM and lead author of the study. (Chew is pictured at the top of this article presenting his findings at a conference in Vancouver.)

Glen Chew, first author of the paper.


Glen Chew, first author of the paper.

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, PhD, 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 Dr. Ndhlovu, an Associate Professor at UH in the Department of Tropical Medicine and Hawaiʻi Center for AIDS.

Lishomwa Ndhlovu, MD, PhD


Lishomwa Ndhlovu, MD, PhD

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. “Because the results were recapitulated in monkeys infected with SIV, the route into HIV clinical use should be much more rapid, since the pre-clinical studies can be done immediately” said Dr. Sacha, Assistant Investigator at OHSU.

According to the World Health Organization (WHO), since the beginning of the epidemic, almost 78 million people have been infected with the HIV virus and about 39 million people have died of HIV. Globally, approximately 35.0 million people were living with HIV at the end of 2013 and an estimated 0.8% of adults aged 15–49 years worldwide are living with HIV. There is no approved vaccine or curative treatment.

Currently an estimated 2,900 people in the Hawaiian islands are living with HIV/AIDS with many others unaware of their HIV status. The Hawaiʻi Center for AIDS has launched a fundraising campaign, “Hawaiʻi to Zero” (H20) Initiative, to raise additional resources in its mission to discover a cure for HIV. Learn more about the H20 initiative at: http://hawaii2zero.jabsom.hawaii.edu/

Additional Information:

The research by Chew and his colleagues was supported in part by the National Institutes of Allergies and Infectious Diseases (NIAID) (RO1 AI087145, K24 AI069994), the UCSF Clinical and Translational Research Institute Clinical Research Center (UL1 RR024131), and the CFAR Network of Integrated Systems (R24 AI067039). Additional support came from the National Center for Research Resources (NCCR) grant P51 OD011092 and the NIAID grant P30 AI027763. Funding was also made possible by collaborative efforts of the Office of AIDS Research, the NIAID, and the International AIDS Society (L.C.N.). Additional support was provided in part with federal funds from the NIAID and NIH contract Number NOI-AI-85341. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

The complete list of authors:
Glen M. Chew1, Tsuyoshi Fujita1,2, Gabriela M. Webb3,4, Benjamin J. Burwitz3,4, Helen L. Wu3,4, Jason S. Reed3,4, Katherine B. Hammond3,4, Kiera L. Clayton5, Naoto Ishii2, Mohamed Abdel-Mohsen6, Teri Liegler6, Brooks I. Mitchell1, Frederick M. Hecht7, Mario Ostrowski5, Cecilia M. Shikuma1, Scott G. Hansen3,4, Mark Maurer8, Alan J. Korman8, Steven G. Deeks7, Jonah B. Sacha3,4* and Lishomwa C. Ndhlovu1* 1Hawaiʻi Center for AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaiʻi, Honolulu, HI 96813, USA; 2Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980- 8575, Japan; 3Vaccine & Gene Therapy Institute and 4Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR 97006, USA; 5Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; 6Division of Experimental Medicine and 7HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94110, USA; 8Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA 94063, USA.

The full PLoS Pathogens article is posted on-line at:
PLos Pathogens Article

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