HIV : ART leaves unrepaired holes in the immune system’s wall of defence

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If they don’t receive antiretroviral therapy (ART), most HIV patients see a progressive weakening of their immune system.

But a very small percentage of patients – 0.3% – spontaneously control the virus themselves, without ART.

Could an explanation lay partly in the sets of genes expressed by scarce white blood cells that recognize HIV?

Yes, according to a study published in Nature Immunology and conducted by researchers at the University of Montreal Hospital Research Centre (CRCHUM).

Critical for the coordination of immune responses, CD4 T cells are important white blood cells (lymphocytes) that help control chronic infections like HIV.

But on average only about one cell in 1,000 in the CD4 T cell population can recognize the virus.

“With my research team and my collaborators, we comprehensively determined the entire set of genes expressed by these rare cells from the blood of people chronically infected with HIV in whom the virus was abundant prior to ART,” said Daniel Kaufmann, a CRCHUM researcher and an infectious disease specialist.

“We then compared it to the cells of HIV controllers, infected people who control the virus in the absence of therapy.

This type of powerful approach, also called genome-wide transcriptional profiling, measures the activity of thousands of genes at once, thus creating a global picture of cellular function.”

Using sophisticated cell analysis techniques, lead author Antigoni Morou, a postdoctoral fellow in Kaufmann’s lab, identified major functional differences between the two groups of patients in the study.

The HIV controllers had much more robust immune responses, known as Th17 and Th22, which are important for the defence of the gastrointestinal tract, for example.

But chronically infected patients with high levels of viral replication showed dysregulated CD4 T cells targeting HIV, and some of their cell subsets showed signs of abnormal functioning.

New therapies ahead?

Continuing their investigation, the CRCHUM scientists wondered whether ART leads to an immune response akin to the one found in HIV controllers.

“We followed up chronically infected patients after control of the virus by ART and checked if the treatment can ‘repair their immune system’ and allow them to have CD4 T cells with features similar to those of the HIV controllers,” said Kaufmann, a professor at Université de Montréal.

The result was double-edged: some gene modules were sensitive to ART, while others turned out to be expressed very differently than in HIV controllers.

“We showed that ART leaves unrepaired holes in the immune system’s wall of defence,” said Kaufmann.

“Our results suggest that some of these long-lasting defects may contribute to the lack of viral control once the antiretroviral therapy is interrupted. We now know which holes linger in the immune system.

Do we have to fill them in, and if so, how? This is another science question.”

Paving the way to new therapies that could complement ART, Kaufmann’s team identified important features of an effective HIV specific immune response compared to a dysfunctional one and showed how the response can be affected by ART.

The next step will be to study the underlying programming of these CD4 T cells (epigenetics) in the hope of developing new targeted strategies to reverse immune dysfunction and complement ART. Kaufmann’s lab is now using the same approach to evaluate candidates for an HIV vaccine.

In 2017, nearly 37 million people were living with HIV. Every day, 5,000 new infections are reported to health authorities around the world.


What Is HIV Treatment?

HIV treatment involves taking medicines that slow the progression of the virus in your body. HIV is a type of virus called a retrovirus, and the combination of drugs used to treat it is called antiretroviral therapy (ART).

ART is recommended for all people living with HIV, regardless of how long they’ve had the virus or how healthy they are. ART must be taken every day, exactly as your health care provider prescribes.

Why Is HIV Treatment Important?

Getting and staying on HIV treatment because it reduces the amount of HIV in your blood (also called the viral load) to a very low level.

This keeps you healthy and prevents illness.

There is also a major prevention benefit. People living with HIV who take HIV medication daily as prescribed and get and keep an undetectable viral load have effectively no risk of sexually transmitting HIV to their HIV-negative partners.

This is called treatment as prevention.

If left untreated, HIV attacks your immune system and can allow different types of life-threatening infections and cancers to develop. If your CD4 cell count falls below a certain level, you are at risk of getting an opportunistic infection.

These are infections that don’t normally affect people with healthy immune systems but that can infect people with immune systems weakened by HIV infection. Your health care provider may prescribe medicines to prevent certain infections.

HIV treatment is most likely to be successful when you know what to expect and are committed to taking your medicines exactly as prescribed. Working with your health care provider to develop a treatment plan will help you learn more about HIV and manage it effectively.

When Should You Start HIV Treatment?

Treatment guidelines from the U.S. Department of Health and Human Services recommend that a person living with HIV begin ART as soon as possible after diagnosis. Starting ART slows the progression of HIV and can keep you healthy for many years.

If you delay treatment, the virus will continue to harm your immune system and put you at higher risk for developing opportunistic infections that can be life threatening.

Does ART Cause Side Effects?

Like most medicines, antiretroviral therapy (ART) can cause side effects. However, not everyone experiences side effects from ART.

The HIV medications used today have fewer side effects, fewer people experience them, and they are less severe than in the past. Side effects can differ for each type of ART medicine and from person to person.

Some side effects can occur once you start a medicine and may only last a few days or weeks. Other side effects can start later and last longer.

If you experience side effects that are severe or make you want to stop taking your HIV medication, talk to your health care provider or pharmacist before you miss any doses or stop taking the medication. Skipping doses or starting and stopping medication can lead to drug resistance, which can harm your health and limit your future treatment options.

Some side effects of ART that are most commonly reported include:

  • Nausea and vomiting,
  • Diarrhea,
  • Difficulty sleeping,
  • Dry mouth,
  • Headache,
  • Rash,
  • Dizziness,
  • Fatigue, and
  • Pain.

And be aware; HIV medicines also may cause different side effects in women than men.

Contact your health care provider or pharmacist immediately if you begin to experience problems or if your treatment makes you sick.

If side effects make you want to skip taking your medications sometimes or stop taking them altogether, talk to your health care provider or pharmacist right away to find solutions that work for you.

Your health care provider may prescribe medicines to reduce or eliminate side effects or may recommend changing your medication to another type of ART that might work better for you. 

Learn more about the possible side effects of ART and ways to manage them.

What Is HIV Drug Resistance?

Drug resistance can be a cause of treatment failure for people living with HIV. As HIV multiplies in the body, it sometimes mutates (changes form) and produces variations of itself. Variations of HIV that develop while a person is taking ART can lead to drug-resistant strains of HIV.

With drug resistance, HIV medicines that previously controlled a person’s HIV are not effective against new, drug-resistant HIV.

In other words, the HIV medicines can’t prevent the drug-resistant HIV from multiplying. Drug resistance can cause HIV treatment to fail.

A person can initially be infected with drug-resistant HIV or develop drug-resistant HIV after starting HIV medicines. Drug-resistant HIV also can spread from person to person. Drug-resistance testing identifies which, if any, HIV medicines won’t be effective against your specific strain of HIV. Drug-resistance testing results help determine which HIV medicines to include in an HIV treatment regimen.


More information: Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease, Nature Immunology (2019). DOI: 10.1038/s41590-019-0418-x

Journal information: Nature Immunology
Provided by University of Montreal

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