Breakthrough HIV Research: A Real Step Closer to a Cure. Advances in Lipid Nanoparticles

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A major breakthrough in the search for a cure to HIV was just made. Dr. Paula Cevaal at the University of Melbourne published an article on her research in Nature Communications last week that may mean a major hurdle in completely eradicating HIV has possibly just been crossed which could lead to new treatment modalities with the goal of completely removing all traces of the virus from someone who has been infected. Today we will go over what the study showed and what it means in terms of the possible final steps towards a cure.

The study evaluated a new way of delivering mRNA into T cells which have HIV latency and this may not seem exciting on the surface, but let’s do a quick refresher on why HIV hasn’t been able to be cured yet before we talk about what this next step means.
So right now the current treatment for HIV is HAART or highly active anti retroviral treatment. These drugs act to disrupt the different steps in which HIV is able to replicate itself inside of cells, preventing new copies of the virus from being created. This is wonderful in terms of reducing the risk of transmission and preventing the progression of the disease as it can drastically reduce the viral load also known as the number of copies of the virus circulating in someone’s blood stream to the point of being undetectable.
Great right? So why doesn’t this completely remove the virus and cure the disease if it can no longer make new copies? Well the problem is HIV is a retrovirus which means it actually integrates itself into a person’s DNA where it can hide indefinitely in a latent state. The virus can just sit there undetected and then later start replicating again at a future time, but as long as the virus isn’t replicating the antiretroviral medications can’t do anything to completely get rid of it. The main cell line that acts as a reservoir for latent HIV is memory CD4+ T cells which are a type of lymphocyte or white blood cells which help our body make an immune response.
So then how do you get to these hidden copies of HIV? Well since recent breakthroughs in mRNA treatments, like with the recent coronavirus vaccines, scientists thought that mRNA could act as an LRA or latency-reversing agent or basically something that forces the initiation of the transcription of latent HIV virus, basically turning it back on so it is no longer hidden. So then what is the problem if we can use mRNA to restart the virus, why haven’t we done it yet?
The issue has been actually getting that mRNA to where the viral DNA is. Just injecting someone with it does not mean that it is going to be taken up by cells and especially the specific CD4+ T cells. So to try to get these cells to take up the mRNA scientists tried putting it inside a lipid nanoparticle or LNP. For those of you who don’t know much about cell biology, cells have a wall made of a phospholipid bilayer which is a double layer of fat that stops most things from crossing into cells. It’s made of fat the outside of cells is mostly water and those two don’t like each other so things stay separate. A lipid nanoparticle is a sphere made with a wall of lipids that can hold something inside. By using these you can then get cells to grab onto them and absorb them, and then have their contents released inside the cells.
The only problem with this was that the previous lipid nanoparticles could enter cells, but could not target CD4+ cells in a way that was potent enough to initiate transcription properly. Now this is where this research paper comes in. The researchers believed that if they could modify the composition of the lipids that they could possibly get it to target these cells better and as it turns out they could!
After modifying an already existing FDA approved lipid nanoparticle formulation called patisiran they found that they could transfect 76% of CD4+ t cells and that this transfection was successful in reactivating the latent virus in cells. So why isn’t this now a cure if we can reactivate latent virus? Well it seems like there are still a few things that are preventing this. The first is that the body does not seem to find and clear these newly activated cells and it isn’t clear why but it is thought that there may be a mechanism the virus uses to have the cells avoid being targeted by an immune response. Another is that the HIV reservoir is not just in these CD4+ cells and so those other tissues that could hold the virus also have to be removed. Viral and patient diversity may also be a contributing factor.
This paper represents an important step, but sadly not the final step in finding a cure to HIV. It does however open up several new potential approaches in clearing the virus and we can only hope that it will eventually lead to more promising treatments in the future.
Thanks so much for watching. I am Frank Cioppettini with Servetty Software and I will see you in the next one!

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