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02 May 2019

International research team wins $6M grant to study HIV and tuberculosis co-infection in children

An international team of scientists, including several from the Doherty Institute, are working together to understand how HIV puts children at high risk of contracting and dying from tuberculosis (TB), thanks to a five-year, US$6.2 million grant from the National Institute of Allergy and Infectious Disease.

There are about two million children living with HIV. They are much more likely to develop TB, and about 40,000 HIV-positive children die from TB every year.

The University of Pittsburgh, University of Wisconsin-Madison and University of Hawai’i at Mānoa are leading the project that will fund non-human primate experiments to understand disease mechanisms and explore a potential therapeutic approach.

Principle Investigator, Research Associate Professor of Microbiology and Molecular Genetics at the University of Pittsburgh, Charles Scanga, Ph.D., said children have distinct immune responses.

“Our first goal is to check whether we see in kids what we have already shown in adults, in a model of kids who may go many months or years without being diagnosed, which is the unfortunate clinical reality in underserved parts of the world,” Associate Professor Scanga said.

Scanga hypothesises that simian immunodeficiency virus (SIV) disrupts the normal function of the natural killer T cells and mucosal-associated invariant (MAIT) cells in the lungs that could act as a first defense against TB.  In response, these cells produce more of the protein PD-1, which leads to immune exhaustion and failure to respond to invading bacteria.

The next step is to see whether it’s possible to reverse immune exhaustion to fend off TB more effectively. Associate Professor Shelby O’Connor from the University of Wisconsin-Madison is leading this part of the project, in collaboration with the Doherty Institute, where she is currently on sabbatical.

They plan to test a cancer immunotherapy drug, a PD-1 blocker, which reverses immune exhaustion so that T cells might better prevent TB bacteria from infiltrating the lungs.

“It is amazing to me how the interventions for people living with HIV are merging with those used to treat cancer. While the diseases are quite different, there are also many similarities in how an affected person responds to each disease,” Associate Professor O’Connor said.

“We are fortunate to be able to work with our colleagues at the Doherty Institute to further understand how these interventions can improve the way a person living with HIV will respond to tuberculosis.”

Associate Professor O’Connor has teamed up with Professor Stephen Kent, Professor Dale Godfrey, Dr Jennifer Juno, and Dr Amy Chung from the Doherty Institute, and Dr Daniel Pellicci from the Murdoch Children’s Research Institute for their unique and varied expertise.

“All of the connections we have made here have been really valuable, particularly when it comes to studying the unconventional T cell response and antibody responses,”

“The Doherty Institute immunology experts are among the best in the world, and being able to utilise the specialty skills and tool available here is crucial to the success of this project.”

Professor Lishomwa Ndhlovu of the John A. Burns School of Medicine at the University of Hawai’i is extending the project from the laboratory to the field – looking at blood samples from children in Myanmar, where there is a high prevalence of both HIV and TB, in collaboration with Professor Kyaw Linn at the Yangon Children’s Hospital.

The idea is to see whether children living with HIV have the same T cell deficiencies and immune exhaustion markers as the laboratory animals, and whether those markers correlate with TB coinfection rates.

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