More on curing HIV: Cutting-edge approaches that could stop the virus

There were a few points that I didn’t touch on in that last post on the stem cell cure that I’d like to address still.

To review, CCR5 is required for HIV to enter cells. This is why the stem cell transplant worked to cure the Berlin Patient. Since the new transplanted cells only made the defective version of CCR5, they couldn’t be infected by an HIV that remained in the patient’s body.

As is usually the case with HIV, however, things aren’t always that simple. In fact, CCR5 is what’s known as a “co-receptor” for HIV, meaning that it’s more like a sidekick to the main receptor for HIV, which is called CD4. To complicate matters further, CCR5 isn’t the only co-receptor for HIV. There’s another protein called CXCR4 that some strains of HIV can use to get into cells instead of using CCR5.

HIV tropism

For reasons that aren’t well understood, people early on in their infection tend to have HIV that uses CCR5 (called R5 HIV for short), instead of HIV that uses CXCR4 (X4 HIV). That’s why having two copies of the CCR5 delta-32 mutation is so protective against HIV infection – since most infections seem to start out with R5 HIV, which needs CCR5 to get into its target cells.

The type of coreceptor that a given HIV virus uses is called its “viral tropism”. The HIV population in a person can actually change its tropism over time – what’s known as a “tropism switch”. Here’s an article I co-wrote about that topic. So most people tend to start out with R5 HIV, and over time about half of people will develop some level of X4 HIV.

This was something they were a little worried about with the Berlin Patient, since if he had any X4 HIV in his body, it was possible that it would stick around and infect his new transplanted immune system. Even though the new cells didn’t have CCR5 on them for HIV to use, they still had CXCR4. Especially worrying is the fact that X4 HIV tends to be associated with a faster fall in your CD4 count. CD4 cells are the ones infected by HIV, and when they drop below 200 cells per cubic millimetre, that’s when you have AIDS. So they wanted to check the Berlin Patient’s virus to see if there was any X4 HIV around that might be able to re-infect his new immune system (bad), and maybe even kill off the immune cells faster (worse).

High-definition HIV sequencing

The approach they used is a very sensitive method called “deep sequencing”. Basically, this method is able to detect and count all the different “versions” of HIV in the swarm of viruses within a person. It’s like HD for HIV. They looked at a specific part of the virus called the V3 loop, which is the part of HIV that interacts with the coreceptor. Certain mutations in V3 make HIV better able to use CXCR4 as a coreceptor. For example, mutations that give the V3 loop a more positive charge are associated with allowing the virus to use CXCR4 as a coreceptor. We can apply deep sequencing to a blood sample and look to see if there are any low levels of X4 viruses.

Disclaimer: I study the application of deep sequencing to HIV tropism, so I may be biased in thinking that it’s cool that they used it here.  They applied deep sequencing to the Berlin Patient’s virus, looking for any viruses with mutations that are associated with being X4.  2.9% of the viruses in his blood were X4 just before the stem cell transplant.

Luckily, as we know, his HIV didn’t come back. But those 2.9% X4 viruses were the perfect chance for HIV to have made a comeback. It’s likely that there just weren’t enough viruses there to actually re-ignite the infection. The Berlin Patient was taking HAART, and had an undetectable viral load (meaning less than 50 viruses per millilitre), so at most, there were less than two X4 viruses per mL of blood. That’s not many at all, considering someone not taking treatment can have millions of copies of HIV in a single millilitre of blood.

We also know that people with undetectable viral loads are less likely to transmit their HIV to other people. So maybe it worked the same here: the undetectable viral load present in the Berlin Patient before the transplant was not enough to infect the “new” immune system he had after the transplant.

Other curative strategies

As I said in the last blog post, having a stem cell transplant to cure an HIV infection is no walk in the park, and not really feasible as a large-scale cure. There are, however, a few approaches to curing HIV that I’d like to discuss. As you can imagine, there are a number of challenges with curing HIV. These are all a long way away from actually being rolled out as common cures, but they’re worth talking about anyway.

What about treatment?

When HAART first came along, many expected that it would be a cure for HIV. The idea was that if you could keep the virus from replicating and infecting new immune cells within a patient, eventually all the infected cells would die off and the patient would be cured. People expected that if we kept the viral load low enough for long enough that eventually people would be cured.

They thought that treatment, which made the viral load fall, would result in the virus travelling along the red arrow in the figure and disappearing when the last of their infected cells died off.

However, we later discovered that the virus followed the green arrow. It remained at a very low level in the blood, but never completely disappeared. When people went off treatment – even after years of having undetectable amounts of virus in their blood – the HIV came back, and had bad effects on their health compared to people who stayed on treatment.

 

Zinc finger nucleases

Zinc finger nucleases are pretty cool little proteins. They’re essentially “molecular scissors” that can be targeted at certain genes to cut them up. One group used them to treat a patient’s OWN cells. The zinc finger nucleases cut up the gene for CCR5 and render it useless. It’s sort of like making your cells have something similar to a CCR5-delta-32 mutation even though you didn’t inherit it.

That approach has now been converted into a clinical trial that is going on right now in people with HIV. This super futuristic approach could in theory be a similar, but better, alternative to the CCR5-delta-32 stem cell cure, because it would do basically the same thing (take CCR5 out of the picture), but using your own cells rather than cells from a donor. This would remove the worry about graft versus host disease, since your own cells would be treated with these “scissors” and put back into you.

Therapeutic vaccines

Therapeutic vaccines are different from the typical HIV vaccines most people talk about (the ones that prevent infection). Therapeutic vaccines are for people who are already positive. The idea behind them is to make a person’s immune system target the parts of HIV that would be most effective in controlling the virus. And there have been some interesting recent developments in this area which suggest that this approach could be useful.

There seem to be better places for an immune system to target HIV compared to other places. For example, proteins in cells called HLA pick up pieces of HIV and display them to the immune system to say “HEY! I’m an infected cell! Kill me!”. And this mechanism can have significant impacts on how high the viral load gets. Some HLA genes (which we inherit from our parents) are better at fighting HIV than others. Different HLA proteins display different parts of HIV, so the part that gets displayed may have an impact on how effective the immune system is at recognizing that HIV is in a cell, and how effective it is at getting rid of that cell.  So, if we can make an immune system target THOSE areas of HIV, instead of other less effective places to target, that could be a major hit to HIV’s ability to replicate itself.

Therapeutic vaccines are probably not the best example of a “cure”, however. This approach could possibly bring HIV down to very low levels, such that treatment might not be necessary any more, but that might not satisfy the strictest definition of a “cure”, which is complete disappearance of the virus – eradication. Although they might be effective at decreasing viral load, they don’t really deal with the main problem of curing HIV, which is HIV latency.

HIV latency

HIV is hard to cure because it zips its genome into OUR own genomes in cells (a process known as integration). What this means is if HIV has integrated into a quiet, sleeping cell (known as a “latent” infection), it can sit comfortably in the cell’s genome, waiting to emerge later when the time is right, like if the virus’ host stops taking their antiretroviral medication. This means that these latently infected cells can act as a viral reservoir to allow the virus to come back later on. The trick with a cure is to somehow find those cells that harbour the virus, or to wake those cells up so they spurt out some HIV and die in the process.

HDAC inhibitors

One of the reasons that a cell is latent, is because it’s not making new proteins – at least not many compared to active cells. This is partly because the cells genes are all coiled up, so they can’t do the usual job that genetic DNA does, which is providing the instructions for making proteins.

Histone deactytalase (HDAC) modifies proteins (called histones) which coil up the DNA. HDAC inhibitors act against HDAC and tell the DNA to “relax”. You might even call HDAC inhibitors Frankie.

By inhibiting HDAC, we can “tickle” the cells (a term I’ve borrowed from Science writer, Jon Cohen) into making virus again. Once the infected cells are tickled awake, they produce virus, and in doing so, they die. Cells that were once latently infected start making virus and get killed off in the process.

The antiretroviral therapy that patients would most likely be taking at the same time would hopefully prevent these new viruses from infecting new cells. So, if all of the latently infected cells could be woken up and killed in the process, we could have a real cure, when there were no more cells around to make new virus.

All these approaches are a long way off from being effective cures, but they’re pretty exciting approaches to dealing with HIV.

Of course, an ounce of prevention is worth a pound of cure, and there are lots of prevention tools, like condoms, safer ways to inject drugs, microbicides, vaccines and even treatment as prevention! Some of these tools, like vaccines, are not as far along as tools like condoms, but anything we can add to the tool box is OK by me!

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