Researchers ID new cells involved in detecting & initiating HIV immune response

For the first time, researchers at The Westmead Institute for Medical Research (WIMR) have identified two subtypes of Mononuclear Phagocyte (MNP) cells that play important roles in detecting then transmitting HIV virus. Importantly these cells play a vital role in switching on an immune response. This discovery is an important step in identifying cells that could be targeted with a HIV vaccine.

WIMR’s HIV research team Jake Rhodes, Prof Andrew Harman and Dr Kirstie Bertram

This study, published in Nature Communications is a continuation of previous work published by the WIMR team, focusing on the important role of MNPs in instigating an immune response to HIV.

What are MNPs?

Post-doctoral researcher and first author on this study, Jake Rhodes said that MNPs in human tissue are specialised at detecting a pathogen and delivering it to the primary target cells in the immune system.

“In the case of HIV, MNPs detect and deliver the virus to CD4T cells, which then help to coordinate an immune response by stimulating other cells to fight the virus.”

“Most studies looking at the role of MNPs in the transmission of HIV have focused on MNPs located at the epithelial level – the thin tissue that forms the outer layer of the body. However, trauma and inflammation of the mucous membrane are known to be strongly associated with HIV transmission, so our team examined the role of sub-epithelial MNPs, located in the underlying deeper tissue layers.”

What did the study find?

Second author on this study, Dr Kirstie Bertram explains that, for this study, the WIMR team used actual anogenital tissue samples, donated post-surgery for research purposes. “The cells in these tissues behave differently to cells in other parts of the body, so being able to use actual tissue samples was vital.

“Our research showed that HIV can penetrate the epithelial surface to interact with sub-epithelial MNPs in anogenital tissue samples.  Using advanced technologies, our team was able to watch as these MNPs took up HIV within 30 minutes of exposure to the virus.”

HIV cell image – langerin+ cDC2 taking up HIV in human inner foreskin after two hours

The team were able to define the full range of MNP subsets that are present in human anogenital and colorectal tissues, and that encounter HIV during sexual transmission of the virus.

As a result, the team was able to identify two MNP subsets that take up the HIV pathogen, become infected, and then transmit the virus to CD4T cells.  The subsets identified are:

  • CD14+CD1c+ monocyte-derived dendritic cells
  • Langerin-expressing conventional dendritic cells 2.

A senior researcher on this study, Associate Professor Andrew Harman says that, compared with other MNPs, both subsets took up HIV more efficiently and became more infected.

“We found that CD14+CD1c+ monocyte-derived dendritic cells were most efficient at transferring HIV to CD4T cells at late time points.  However, we discovered that Langerin-expressing conventional dendritic cells 2 transferred the virus more effectively at early time points.

“These findings are important because, to develop a HIV vaccine, we need to understand which dendritic cell subsets pick-up HIV and switch on the immune response.  A vaccine would target these subsets of cells.”

– Associate Professor Harman.

What are the next steps?

There is no vaccine or cure for HIV/AIDS. A HIV vaccine is vital to reducing the impact of HIV which is now, in most cases, transmitted sexually.  With around 37 million people infected globally, and 1.8 million new infections each year, finding a vaccine remains a priority for researchers.

While antiretroviral therapy (ART) is efficient at controlling HIV infection, it is a lifelong treatment which is costly and is associated with toxicities.  Only 57% of HIV positive individuals receive ART.

Associate Professor Harman says, “ART can also be given to healthy ‘at risk’ individuals as pre-exposure prevention, and this has been shown to be effective in reducing transmission. However, this is not a global solution due to lack of access in low income countries, and variable uptake in Western countries. In addition, preventative treatment has recently been shown to be ineffective in situations where the mucous membrane is inflamed, as is normally the case with sexual transmission of HIV.”

The WIMR team’s next steps will seek to further understand the mechanisms by which these MNP cells interact with HIV.

Jake Rhodes says, “Our next steps are to define the precise receptors that these cells use to bind HIV, with the aim of blocking the transmission of HIV and these receptors.  We will also seek to identify exactly how these cell types activate the immune system, and what they do once they have encountered HIV.”

Beyond Insulin

Insulin was first discovered 100 years ago, and 2022 marks its 100th year treating people with type 1 diabetes. But we may be on the cusp of a new treatment that could significantly reduce the need for insulin in newly-diagnosed patients.

January 2022 marks a century since insulin was first used to treat Leonard Thompson, a 14-year-old dying of type 1 diabetes. The then experimental treatment saved Leonard’s life.

Leonard needed insulin because his body’s immune system had targeted and destroyed the insulin-producing cells in his pancreas, meaning his blood sugar levels were not able to be controlled.

“Type 1 diabetes is still treated today by replacing insulin. To stay alive, people with diabetes are dependent on insulin replacement – given by multiple daily injections or an insulin pump – along with frequent blood glucose measurements,” explains Professor Tom Kay, Director, St Vincent’s Institute of Medical Research (SVI) and an internationally-renowned diabetes researcher.

But while lifesaving, insulin treatment has limitations.

A new approach

“The long-term complications of type 1 diabetes include heart attack, stroke, vision impairment, kidney disease and nerve damage – it is a significant condition,” says Tom. “Our century-old approach to managing this disease does not address its underlying cause: the processes which lead the body’s immune cells to destroy insulin-producing beta cells.”

A clinical trial being led by SVI aims to change that.

Dubbed “BANDIT” (BAricitinib in New onset type 1 DiabeTes), the trial is investigating whether baricitinib – a drug used to treat rheumatoid arthritis – can protect insulin-producing beta cells from immune attack.

“Our aim is to retain those beta cells still present when type 1 diabetes is first diagnosed, and prolong the body’s own production of insulin,” says Professor Helen Thomas, BANDIT co-investigator and Head of the Immunology & Diabetes Unit.

“If this trial proves successful, people with type 1 diabetes could be significantly less dependent on insulin treatment. That would herald a massive change in type 1 diabetes care.”

BANDIT trial explainer:

(article continues below video)

The researchers

Some of the nation’s top type 1 diabetes clinical researchers are collaborating on the BANDIT trial with SVI. They include Associate Professor John Wentworth at The Royal Melbourne Hospital; Professor Fergus Cameron, Director of the Department of Endocrinology and Diabetes at The Royal Children’s Hospital Melbourne; Professor Richard MacIsaac, Director of Endocrinology and Diabetes at St Vincent’s Health and Professor Jennifer Couper, who heads the Diabetes and Endocrinology Department at the Women’s and Children’s Hospital, Adelaide.

“We’re optimistic that with the support of our generous trial participants and the expertise of these outstanding clinicians, we will see positive results,” says Helen. “We are very hopeful of being able to change the lives of people diagnosed with type 1 diabetes in future.”

“That would be a dream come true for us, and for those patients.”

Recruitment for this clinical trial has now closed. However, more information is available at www.svi.edu.au/bandit

Anders puts his hand up for type 1 diabetes

“Will I still be able to surf big waves?”

That was Anders’ first thought when he was diagnosed with type 1 diabetes at the age of 29.

Anders was concerned he may not be able to surf anymore

“I’d lost about 10 kilos in six weeks. My gut feel was there was bound to be a simple explanation and I wasn’t that concerned, but my girlfriend encouraged me to go see a doctor.”

“I had other symptoms, in hindsight. My mouth was very dry, and I was drinking lots of water, but it didn’t occur to me to mention this to the doctor.”

Helping other patients was a key motivator

Anders was the second person to be enrolled in SVI’s BANDIT clinical trial. The drug baricitinib is approved globally for rheumatoid arthritis patients, but SVI researchers have discovered that it may also stop the immune system from attacking insulin-producing cells in the pancreas.

Friends and family had told Anders about the trial after hearing about it in the media. Anders said he immediately considered enrolling, for a few reasons.

“The more altruistic reason was that I could play a role in research that could potentially help people diagnosed with type 1 diabetes in future. Having just been diagnosed, I understood how very tough it could be.”

“Secondly, I really hope this works and makes the rest of my life easier to manage. I realise there’s a chance that I may be one of those participants who is getting the placebo drug, but at the end of the day.”

“I’m getting great care, and contributing to what I think is an important research project.”

Riding the wave

Like his type 1 diabetes diagnosis, taking part in a clinical trial raised many questions.

“The endocrinologist who is leading the trial at the hospital was very reassuring. He walked me through the questions I had about the information and put it into more familiar terms for me.”

While he is hoping his participation in the trial may see his glucose levels stabilise, Anders is happy to report that he has indeed managed to find a way to keep enjoying surfing big waves.  “That’s been a really positive revelation,” he notes.

Anders is now learning to ‘ride the wave’ of his type 1 diabetes diagnoses, and he still holds hope that new treatments for people with the disease will be found.

“You just never know when a trial like the BANDIT is going to lead to a huge breakthrough in science, so I would encourage everyone to take part in a clinical trial if they are given the chance.”

Podcast:

The Herald Sun’s podcast ‘The Splash’ with Grant McArthur provided a great explanation of the trial (starting at 40 seconds):

Listen on Apple Podcasts.