Study unlocks secret of common HIV strain

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A discovery that the most common variant of the HIV virus is also the "wimpiest" will help doctors better treat millions of individuals around the world suffering from the deadly disease, according to one of the world's leading HIV/AIDS researchers. The findings were announced today in the journal EBioMedicine.










In a research project he began almost 15 years ago while at Case Western Reserve University, Arts explored how the various strains of the HIV virus advance in the body. He sought out differences in the strains and how those differences might impact treatment.

HIV is a complex and diverse disease, Arts stressed.

"We don't have one virus infecting 33 million people; we have 33 million people infected with 33 million types of viruses," he said. "We can't look at it as a single strain anymore. We need to look at the differences that exist."

HIV Type 1 (HIV-1) and HIV Type 2 (HIV-2) are two distinct viruses. Generally, when people speak about HIV, they are referring to HIV-1. HIV-2 is relatively uncommon outside of West Africa. Strains of HIV-1 are classified into four groups – Group M, N, O and P. Of those, Group M – or 'Major' – is responsible for the majority of global HIV cases.











Within Group M, there are nine genetically distinct subtypes – A, B, C, D, F, G, H, J and K. The dominant subtype in the Americas, Western Europe and Australasia is Subtype B. As a result, the majority of HIV clinical research has been conducted in these populations despite the fact they represent only one in 10 global HIV infections.

In contrast, less research is available for Subtype C, although just under half of all people living with HIV have that subtype. The subtype is common in the countries of southern Africa, as well as in the horn of Africa and India.

In screening approximately 300 women in Zimbabwe, Thailand and Uganda newly infected with HIV starting in the early 2000s, Arts and his team studied the length of time it took the disease to go from HIV infection to AIDS. He found Subtype C replicated poorly and slowly in patients – earning it the 'wimpy' moniker among its fellow subtypes.

"This study was a once-in-a-lifetime opportunity for the world to see how patients progress to AIDS and the reasons why. We could analyze the disease progression until they reached AIDS, which is when we started treatment," said Arts, noting this progression took anywhere from five to nine years.

Currently, such a study would be considered unethical, he added, as treatment now starts much earlier for HIV-infected patients. His team was among the first to bring treatment for AIDS patients, in advance of any global treatment programs arriving in Africa.

Graduate student Colin Venner, who assisted Arts with the research, said they would put Subtype C into "boxing matches" in a controlled lab environment to test its strength against other subtypes.

"We don't really have a way to directly visualize what's going on. But once we pull it out, we can see who wins and, in fact, Subtype C is 'wimpy' because it will always be competed to non-existence," Venner said. "We won't be able to find Subtype C at all in these cultures in many cases. It is 100-to-1,000-fold less able to replicate than some other subtype strains."

Subtype C has exploded since the early 1990s, added Venner, drawing many to conclude it would be the strongest virus subtype. However, the HIV virus is usually transmitted during the period patients show no symptoms and are thereby unaware of their condition. A slowly revealing subtype, like Subtype C, might be more likely to be spread given a longer period of no symptoms.

"The longer a patient is asymptomatic, the more likely they may be to transmit it is one of the thoughts that we're working on right now," Venner said.

With Subtype C being the dominant strain in the HIV population, Arts' findings may soon have an impact on potential treatments for HIV patients.

"Knowing the differences in virulence (the capability of a microorganism to cause disease) of these different subtypes has an impact on how we treat with drugs and how we administer vaccines throughout the world," said Arts, adding, unfortunately, there is still no vaccine effective in protecting against HIV. "But, in treatment, if we know a patient progresses very slow to disease and the virus is having a minimal impact on the immune system, all the devastating consequences of delaying treatment, as we saw in North America, may not be as pronounced in patients infected with Subtype C."

These potential treatments, however, don't come without some ethical debate.

"When we're looking at billions and billions of dollars a year to treat the global epidemic, we might have to look at it as to who needs treatment immediately and who can be delayed," Arts said. "That's very controversial but it is something we have to consider."

 

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(CNN)In South Africa, a rare group of children unknowingly find themselves resistant to the effects of HIV.

Even without antiretroviral treatment, they will never develop AIDS, or so scientists believe.
Unlike adults and other children who succumb to the virus if not treated -- enabling it to attack their immune cells and weakening their immunity to disease -- these kids harbor huge amounts of HIV within their blood but remain unscathed.
In fact, they're healthy.
The only reason doctors discovered these children, known as HIV non-progressors, is because their blood is routinely tested, as their mothers had the virus, and they were most likely infected in the womb. This mode of transmission is itself now rare, as it is standard practice around the world for pregnant women to be tested and treated for HIV to avoid infecting their children, known as prevention of mother-to-child transmission.


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"These kids are usually identified incidentally," saidPhilip Goulder, a professor of immunology at the University of Oxford who has been studying 170 of these children, ages 5 and older, in South Africa in hopes of understanding how they stay healthy.
As of September 2016, guidelines changes meant that any child infected with HIV -- irrespective of their health status -- must be given treatment, so the children are now, or soon will be, receiving antiretroviral treatment. But the fact remains that they were able to defend themselves naturally, and Goulder's latest study, analyzing their blood samples, has partly discovered how.
"The critical factor was that they had very low levels of immune activation," Goulder said. "We saw a failure of HIV to activate the immune system."
Going against immunity
You might imagine that a poor immune response would help a disease flourish and invade the body, as there would be nothing attacking it. But when it comes to HIV, the virus thrives by infecting and destroying the immune cells themselves. It must insert its own genetic material into them to proliferate and produce more viruses.
"Usually, you get more and more activation (of immune cells), so you get more and more infection," Goulder said. "It's a cruel circle."


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When people are not on treatment, this increasingly damaged immunity makes them susceptible to infection through acquired immune deficiency syndrome, or AIDS. But in non-progressor children, there is no destruction of the immune system, and therefore, no AIDS.
Goulder wanted to see "what immune responses prevent HIV disease progression in these children," he said, and the answer came in two parts: the reduced immune activation as well as less infection of certain immune cells, known as long-lived CD4 T-cells, which are typically infected -- and destroyed -- by HIV. Unlike the short-lived versions, the long-lived forms replenish the general stock of these cells within the body, so if they stay in shape, so does their supply.


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"It's difficult for the virus to get into (them), so they remain relatively unscathed," said Goulder.
And it gets more detailed, as the team also thinks it has cracked why the virus can't enter.
Non-progressors have lower levels of a receptor protein called CCR5, which sits on the surface of CD4 T-cells. This is where HIV particles attach to enter and destroy the cells, so fewer of these means fewer viruses getting in. The technique is the same as seen in monkeys, such as sooty mangabeys, which have natural protection against the monkey version of HIV, known as Simian Immunodeficiency Virus.
"Both sooty mangabeys and (child) non-progressors can replace any CD4 cells, as the number of long-lived cells that die is low," said Goulder.

This defense method, in which HIV is left floating in the body, unable to infect its target cells, is unique.
Child non-progressors represent just 5% to 10% of children infected with HIV, and others infected when young experience quite the opposite effect, with a much faster progression to AIDS than any adult. They have a 60% death rate within two years if they are not on treatment, according to Goulder, whereas adults would have 10 years, on average, before the onset of AIDS and 11 years before death.
There are some adults who are naturally immune to AIDS, known as elite controllers, but they represent just 0.3% of adults infected with HIV, and their approach to control is pretty much the opposite. "These adults achieve being disease-free by mounting a very strong (immune) response against the virus," Goulder said. Essentially, they bombard and attack to get what they need.
But in kids, Goulder has now showed that the right way to go is to avoid getting an immune response, by "not picking a fight with a virus that you're going to lose," he said.
This could bring a whole new approach to HIV control.
Mimicking the monkeys
"(Scientists) used to say, 'If only humans can be like monkeys, then HIV wouldn't be a problem,' " said Robin Shattock, professor of mucosal infection and immunity at Imperial College London, who was not involved in the study. "And now, here are these children."
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Shattock is leading the European AIDS Vaccine Initiative (EAVI2020) and looking into ways to prevent HIV disease progression. "(We) don't want to treat people for life," he said.
Since it was discovered in 1996, antiretroviral treatment has had a huge impact on the HIV epidemic, with current combination therapies resulting in viral levels that are undetectable in most, and studies showing they can reduce sexual transmission by 96%. So researchers dare not suggest another method of treatment -- at least, not yet.
"We want to find a way to eliminate the virus and cure people, but this is a pretty tough call," Shattock said. "If you can protect these central (T-cells), you might be able to achieve long-term remission. ... The question is, how can you convert someone into a non-progressor?"
Shattock believes this new finding provides a different avenue to reach this goal. "This shows that humans have found an alternative way to cope with HIV infection," he said, warning that a lot more understanding is needed to even start going down this road.
"There's a lot to follow up on," he said. "(But) this gives a biological road map to start to verify the science."