“We know that obesity in adults is linked with more than 200 different diseases. Research tells us that in obesity the immune system becomes overactivated, which damages tissues in the body, and some immune cells become depleted so they can’t protect properly. I want to see how we can protect children living with obesity from these immune system changes, to protect them against future disease and damage.

How did you get into this area of research?

I am the first person in my family to go to university. I went to Maynooth University through the access programme, then after my PhD I worked as a Newman scholar with Donal O’Shea and Lydia Lynch in University College Dublin.

We were interested in a type of cell in the immune system called the invariant natural killer T-cell. It attacks viruses and tumours, but stops working properly in obesity. When I moved back to Maynooth to set up my own research group, I thought it would be interesting to look at immune changes in younger people living with obesity.

What did you find when you looked at children with obesity?

We did a project with the National Children’s Research Centre, where we worked with children living with obesity at age six, 10 and 16. We could see kids as young as six were starting to show signs of chronic inflammation, a type of immune-system overactivation.

They already had molecular markers of it in their bloodstream. I thought maybe if we can intervene with children who are living with obesity and stop this immune activation, turn down the chronic inflammation, we could perhaps delay or reduce related disease in adulthood.

We are looking at options there, using a gut hormone that is known to tone down chronic inflammation. There is a shorter-term outlook too: in another project we are looking at obesity and vaccinations.

Tell us more about that.

We know that some vaccines are less effective in adults with obesity, which makes sense. After all, we have been showing for 15 years that in obesity the immune system is overactivated or exhausted.

So we looked at the responses to childhood measles and rubella vaccinations, and in a small study we found that children with obesity have far less of the antibody titre after vaccinations, which means they may not be as well protected from these diseases. Now we are looking at this more closely in larger numbers of children, and we hope to examine responses to the HPV vaccine too.

What do you love about your work?

I just really enjoy it. Of course there are times when things don’t work out as you expect, but I’m a sunny-side-up kind of person, and you just rethink the experiment or find a new direction.

What do you do to take a break?

I find that exercise is a great way to clear the mind. When I was a teenager I did a lot of kickboxing, I was number one in the world at one point. In the last few years I have been doing CrossFit, and I was involved in opening a gym where I teach classes. It’s one of those things that, no matter how you feel at the start of the class, you will always be happy about having done it afterwards. It’s a great way to unwind.

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Using genetic sequencing, scientists at the University of California, San Diego (UCSD), School of Medicine say they have identified a principal cellular player controlling HIV reproduction in immune cells which, when turned off or deleted, eliminates dormant HIV reservoirs.

“This is one of the key switches that the HIV field has been searching for three decades to find,” said Tariq Rana, PhD, professor of pediatrics and genetics at UCSD School of Medicine. “The most exciting part of this discovery has not been seen before. By genetically modifying a long noncoding RNA, we prevent HIV recurrence in T cells and microglia upon cessation of antiretroviral treatment, suggesting that we have a potential therapeutic target to eradicate HIV and AIDS.”

HIV spreads through certain bodily fluids attacking the immune system and preventing the body from fighting off infections. If left untreated, the virus leads to the disease AIDS.

Antiretroviral therapy is used to prevent and treat HIV. However, the medication does not cure patients. Instead, the virus remains inactive in the body. If therapy is discontinued, the virus awakens and multiplies rapidly.

In a study (“The Long Noncoding RNA HEAL Regulates HIV-1 Replication through Epigenetic Regulation of the HIV-1 Promoter”) published online in mBio, Rana and colleagues report the first genome-wide expression analysis of long noncoding RNA (lncRNA) in HIV-infected macrophages that promote tissue inflammation, stimulate the immune system, and rid the body of foreign debris. In general, lncRNAs do not encode the recipe for proteins the way other RNAs do, but instead help control which genes are turned “on” or “off” in a cell.

The team described how a single lncRNA dubbed HIV-1 Enchanced LncRNA (HEAL) is elevated in people with HIV. HEAL appears to be a recently emerged gene that regulates HIV replication in immune cells, such as macrophages, microglia, and T cells.

Using a combination of genomic, biochemical, and cellular approaches, they found that silencing HEAL or removing it with CRISPR-Cas9 prevented HIV from recurring when antiretroviral treatment was stopped. Additional research to confirm these effects in animal models will be performed.

“A major challenge in finding a cure for HIV-1/AIDS is the difficulty in identifying and eradicating persistent reservoirs of replication-competent provirus. Long noncoding RNAs (lncRNAs, >200 nucleotides) are increasingly recognized to play important roles in pathophysiology. Here, we report the first genome-wide expression analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs). We identified an lncRNA, which we named HIV-1-enhanced lncRNA (HEAL), that is upregulated by HIV-1 infection of MDMs, microglia, and T lymphocytes. Peripheral blood mononuclear cells of HIV-1-infected individuals show elevated levels of HEAL. Importantly, HEAL is a broad enhancer of multiple HIV-1 strains because depletion of HEAL inhibited X4, R5, and dual-tropic HIV replications and the inhibition was rescued by HEAL overexpression,” the investigators wrote.

“HEAL forms a complex with the RNA-binding protein FUS, which facilitates HIV replication through at least two mechanisms: (i) HEAL-FUS complex binds the HIV promoter and enhances recruitment of the histone acetyltransferase p300, which positively regulates HIV transcription by increasing histone H3K27 acetylation and P-TEFb enrichment on the HIV promoter, and (ii) HEAL-FUS complex is enriched at the promoter of the cyclindependent kinase 2 gene, CDK2, to enhance CDK2 expression. Notably, HEAL knockdown and knockout mediated by RNA interference (RNAi) and CRISPR-Cas9, respectively, prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment in vitro. Our results suggest that silencing of HEAL or perturbation of the HEAL-FUS ribonucleoprotein complex could provide a new epigenetic silencing strategy to eradicate viral reservoirs and effect a cure for HIV-1/AIDS.”

“Our results suggest that HEAL plays a critical role in HIV pathogenesis,” said Rana. “Further studies are needed to explain the mechanism that leads to HEAL expression after an individual is infected by HIV, but this finding could be exploited as a therapeutic target.”

The post Critical Cellular Player Controlling HIV Reproduction in Immune Cells Identified appeared first on MyMedicPlus.