Antibodies against HIV: was there a sensation?

Last Thursday, the journal Science published an article by Dennis Burton and colleagues that was trumpeted around the world as a radical breakthrough towards defeating HIV. The “Achilles heel” of the virus has been found! In this article I will try to figure out where the breakthrough is, where the normal progress is and what this all means for work on the vaccine.

First, a little introduction for those who don't know anything about antibodies. Our immune system produces huge numbers of B cells every day, which can synthesize antibodies. The specificity of these antibodies is random and individual for each cell. The B cell floats in the blood for a while, and if it does not come across a microorganism that its antibody can contact, it dies. When a microorganism enters our body, the immune system begins to sort through all the B cells present in the body in search of those whose antibodies can bind to this organism. Such a cell is activated and begins, firstly, to divide, and secondly, to produce antibodies in huge quantities. The primary role of antibodies is to trivially cling to and tag microorganisms (and other foreign substances) in the body. Microorganisms marked in this way are recognized by the immune system and destroyed. This is the main role of antibodies, but in relation to viruses, antibodies also have an important side effect. Since viruses are molecular machines, the binding of an antibody to them sometimes (but not always) disrupts the functionality of this machine: the virus loses its infectivity. Antibodies that bind to the virus are called neutralizing antibodies. Neutralizing antibodies are fairly standard and can be found in almost anyone who has been infected with HIV for more than a year. But due to the high diversity of the virus, the neutralizing effect of these antibodies is usually limited to the specific virus that was in that person.

The paper, published last Thursday, describes how, using new technologies, the authors found two antibodies in one person that had neutralizing activity against a wide range of HIV variants.

First, briefly about the advantages. The find is certainly interesting. Over the past 25 years of HIV research, only four broad-spectrum antibodies have been found. In this work, the authors found two more in about two years, with higher activity and a wider spectrum of action than the previous four.

Now about the cons. This study confirmed what was already known: broad-spectrum neutralizing antibodies are extremely rare. The authors specifically chose a person who was known to have such antibodies in his blood, but after screening 30,000 antibodies from this person, they found only two with a broad spectrum of action (and these two actually turned out to be just variants of each other). In addition, these antibodies have no direct use for vaccine development. That is, they will be very useful for subsequent research, but the step from them to a vaccine is not trivial. If it were trivial, then the vaccine would have been made a long time ago, using the previously found four antibodies with a wide neutralization spectrum.

A short digression about the technologies used. The search for antibodies with the desired properties (not necessarily against a virus) has always been a very long and labor-intensive process. Each B cell produces its own antibody. That is, cells isolated from the blood must be sorted one by one and then find out what exactly they produce. However, in culture, separated from the rest of the immune system, B cells do not live long. In order to grow them and produce antibodies, B cells were first “made immortal” by hybridizing with cancer cells. This process is very complex, inefficient and very time consuming. The resulting “immortal” cells were already sorted one by one and cell cultures were grown from them, which produced antibodies in large quantities. Only at this stage could antibodies be tested for the desired properties (for example, the ability to neutralize the virus). The whole process took years. Two new technologies have allowed it to significantly speed up. First, Theraclone's technology allows B cells to thrive in cell culture as they do in the body: to live long enough and continue to divide. Therefore, B cells can be isolated from the blood and immediately sorted one at a time into a special environment in which they begin to multiply and produce antibodies. The amount of antibodies produced is not very large (approximately 50 microliters), but is quite sufficient for a very sensitive test. This is where Monogram’s technology comes to the rescue, which allows you to test these 50 microliters to neutralize a fairly wide range of HIV viruses. This eliminates the most time-consuming and ineffective step—the hybridization of B cells with cancer cells. In addition, much of the work can be robotic. As I wrote above, the two antibodies obtained were produced in about two years and cost $100K each. It can be expected that in the future both the time and costs of searching for such antibodies will be significantly reduced.

And finally, several options for what benefits these antibodies can bring in HIV research and in the development of a vaccine and why they are worth looking for and highlighting:

Initially, the search for neutralizing antibodies with a broad spectrum of action was motivated by the idea that if we find such antibodies, then it will be possible to find out what exactly on the virus they bind to (the very “Achilles heel”). This Achilles heel could then be synthesized in large quantities and injected into people as a vaccine, because all antibodies produced against the heel would neutralize the virus. This idea had already been tested with previous antibodies and did not work - the “heels” did not provoke almost any immune response at all, let alone a neutralizing one. The reasons for this are not entirely clear, and the ability to study new antibodies may help us understand them.

A somewhat more general approach to this issue is based on understanding why certain antibodies are neutralizing. We still do not know the mechanism of widespread neutralization. Additional antibodies with a broad spectrum of neutralization will allow us to investigate this issue.

Presumably sometime in the future we will know the mechanisms of broad neutralization and then we will be able to somehow use them in vaccine design.

Recently, people have also begun to think that the broad-spectrum antibodies found could be expressed directly in people (rather than trying to induce their appearance using a vaccine). This method involves, for example, injecting DNA encoding the gene for the desired antibody into the muscle. Experiments on macaques and mice (with the already known four antibodies) indicate that, in principle, this can work - experimental animals are protected from the virus. But there are several problems here too. First, this approach did not work in all experimental animals; the immune system of some mistook this antibody for a pathogenic microorganism and began to destroy it. Secondly, trial experiments on already infected people surprisingly showed the lack of effectiveness of antibodies in suppressing the virus. The reasons for this are also not entirely clear. Finally, to date we do not have delivery methods that would allow antibodies to be expressed in sufficient quantities for a sufficiently long time. A few months after the injection, the injected DNA (or other vector) loses its properties and antibody expression declines. This is not suitable for a vaccine.

To sum it all up, this work is definitely a great advance and has the potential to radically increase our ability to study the mechanisms of HIV neutralization, but in order to transform this knowledge into a vaccine, much work still needs to be done.

Egor Voronin
( shvarz.livejournal.com ),
employee Global HIV Vaccine
Enterprise