Elite controllers: Keeping HIV under control

Elite controllers: Keeping HIV under control

Elite controllers are pretty cool. These are very rare people who are infected with HIV but who seem to be able to control the virus themselves without highly active antiretroviral therapy (HAART). In fact, they keep their virus under control so well, and their viral loads are so low that they’re undetectable (similar to people on HAART).

It’s likely that there’s something about their immune systems which allow these elite controllers to keep their virus levels down without medication. There was a recent genome-wide association study (a “GWAS”, pronounced “Gee, wahss”) that looked at the human genomes of a large group of these patients. The GWAS found that the main place in the genome that is connected with being an elite controller is in the set of genes called HLA. There are certain variations in the HLA genes in people that allow their immune systems to keep HIV under control. Variation in these genes are actually the ONLY ones that were significantly associated with being an elite controller.

Below is a Manhattan plot from that study. Manhattan plots are called what they are because, well, they sort of look like a city skyline, with big skyscrapers! Each dot is a basically a place where they saw a difference in the genomes between elite controllers and people who aren’t elite controllers. Any dot above the dotted line is statistically significant (meaning it’s probably not due just to chance).

In this study, there was only one skyscraper: the HLA genes.

Remember from the first Going Viral post that HLA is the gene that people use to “match” organ donations. Well, HLA is also a big part of the immune system. HLA proteins basically sample bits of protein (called peptides) that they find inside the cell. In a happy, uninfected cell, these peptides are just bits of normal cellular proteins. But in cell that’s infected with HIV, the HLA molecules might pick up bits of viral proteins, and show them to the immune system. Specifically, they show them to immune cells called CTL (cytotoxic T lymphocytes), also known as KILLER T CELLS! The HLA molecule and the bit of HIV protein together signal the killer T cells to, well, kill that infected cell. It’s sort of like putting up a white flag to show that you surrender, but instead the cell is putting up a chunk of virus to show that it needs to be killed.

Certain changes in HLA genes make this whole process occur more efficiently, and essentially make the killing of infected cells easier.

HIV behaves differently in elite controllers

A recent study came out in PLoS Pathogens about elite controllers. The study, by Erin H Graf, Angela M Mexas and colleagues, looked at the cells from people who are elite controllers.

They wanted to see if HIV behaves differently in the cells of these people.

One aspect of HIV that makes it so nasty is that it actually sticks its genome into the DNA of our own cells. This is called “integration”. As we’ve talked about before, integration is one of the reasons that HIV is so hard to cure. Integration makes it so HIV can remain quiet and stealthy in a cell, ready to wake up at any time and infect new cells. It’s the reason that when we go off our anti-HIV meds, the virus re-activates and starts reproducing itself again.

When Graf/Mexas and colleagues took cells from elite controllers, and looked for HIV DNA in them.

Now, we should give them big credit for doing this because finding HIV in elite controllers is notoriously difficult to do! (As you’d expect for people who manage to suppress their virus levels down so low).

So when they looked at the these cells, they saw way less integrated HIV DNA in the elite controllers (the triangles) compared to HIV infected people who aren’t controllers. (The circles are for people not on therapy and the squares are for people on therapy).

OK, but when they looked at TOTAL HIV DNA (instead of just the integrated kind), they didn’t find a difference.

Why? What they found was that elite controllers have only small amounts of integrated HIV genomes but extra amounts of unintegrated genomes.

What do these unintegrated genomes look like, you ask? They look like little circles of DNA, sometimes called “episomes”. In the paper they call them “2-LTR circles”. There’s an LTR (long terminal repeat) on each end of the HIV genome, so when you see two LTRs side-by-side, it means that the genome has flipped back onto itself and formed a circle. These circular HIV genomes are also pretty much dead-ends for HIV. When the genome exists in the circular form, it can’t be used to make baby viruses, so it’s kind of useless from the virus’ point of view.

Now, you might think that elite controllers are getting more of these circular HIV genomes in their cells because the elite controller cells are somehow preventing the HIV genomes from integrating. That’s what I thought at first. But being the good scientists they are, Graf/Mexas and colleagues specifically tested the cells to see whether or not HIV could integrate well into the cellular DNA. They actually found no difference between elite controllers and cells from non-elite controllers, in terms of the ability of HIV to integrate itself.

Weird. But the authors discuss a possible explanation for these data. And guess what they think are involved? Killer T cells!

As we discussed above, we know that elite controllers have HLA genes that make it easier for their killer T cells to kill HIV-infected cells. But, the killer T cells can only tell that a cell is infected if it’s producing viral proteins (since these are what get displayed on the HLA molecules). Viral proteins aren’t made at high levels when the HIV genome is stuck in the circular form, so cells with these circular genomes probably won’t be able to signal to the killer T cells that they’re infected.

At the same time, the cells that DO have integrated HIV genomes will be producing lots of viral peptides to display to the killer T cells, so these cells will be killed by the immune system.

Together, this would mean that elite controllers would have fewer cells with integrated HIV DNA (because those cells are being found and killed by the killer T cells), while also having MORE circular HIV genomes that are unintegrated. That’s what they saw in this study, so their hypothesis makes a lot of sense to me.

So basically, one reason that these elite controllers might have low virus levels in them is because:

1) Their “good” HLA genes allow their killer T cells to more effectively target and kill HIV-infected cells that have integrated HIV genomes in them

2) The remaining cells with unintegrated HIV genomes don’t really get detected well by the killer T cells (because they don’t produce a lot of virus protein), but…

3) That’s not a big issue, since the circular, unintegrated genomes don’t make baby viruses very well, which lowers the number of viruses that are floating around in the blood looking to infect the next cell

This information really adds a lot to our understanding of why HIV elite controllers have such low levels of virus, and why they’re able to keep their HIV infection under control.

Comments
3 Responses to “Elite controllers: Keeping HIV under control”
  1. Jacky Ncongwane says:

    Is it true dat elite controller cant have HIV-AIDS ?

  2. Yan says:

    I really like your writing. It is a very nice retell of the scientific literature. Do you know how circular genomes be formed? Are they also need integrase’s help to become a circular genome? Is this event randomly happened?

  3. urban crafts says:

    I am myself a HIV controller since 23 years…very interesting article

    thanks

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