2023-09-05 14:10:37
Very promising, broad-spectrum antibodies can react with the vast majority of HIV particles to cause their destruction by the body. However, it would be a question of making it capable of producing such effective antibodies itself…
This article is the third in the series dedicated to the hopes of HIV-AIDS research, on the occasion of the celebration of 40 years since the identification of the virus.
Antibodies are certainly among the most effective and popular players in our immune system. These Y-shaped proteins; indeed prevent pathogens from acting by binding to some of their surface proteins, but also help to eliminate them. However, antibodies do not all have the same effectiveness, especially once morest viruses. Some can stop a given type of virus, while others are surprisingly versatile, able to neutralize many viral variants. These are called broad-spectrum neutralizing antibodies or bNAbs. And at the Institut Pasteur, as in dozens of laboratories around the world, they are real stars: there are more than 3,000 publications on their subject between 2013 and 2023. “The interest of broad-spectrum antibodies is major because they are powerful, effective at low doses and generally polyfunctional, confirms Hugo Mouquet, director of the Humoral Immunology Unit at the Institut Pasteur. We believe that they are crucial tools for developing new therapies in the context of chronic diseases (influenza, HIV-1 infection, hepatitis B, etc.), as was the case for Covid-19, but also to help in the development of vaccines. »
Broad-spectrum neutralizing antibodies once morest HIV were discovered in the 1990s in people living with HIV, later referred to as “neutralizing elite” patients. And the ability of these antibodies to recognize and neutralize many strains of HIV immediately aroused the interest of researchers, who saw in them THE solution to overcome this multifaceted virus. The fallout will not be instantaneous, but research has confirmed the potential of these super antibodies, capable for some of neutralize more than 95% of the hundreds of HIV variants tested in vitro in the laboratory. And for good reason, not only do these antibodies have good neutralizing capacities, the arms of their “Y” coming to attach themselves to certain proteins preserved in the envelope of the virus and therefore preventing it from penetrating into the immune cells, but they have also very good so-called effector capacities, the stick of their “Y” leading different immune cells to come and cling to it and destroy viruses or infected cells.
Antibodies are real Swiss Army knives of the immune system. They are capable of neutralizing circulating viruses entering or leaving target cells, of eliminating infected cells, and of stimulating immune responses by forming complexes with viruses.
Hugo Mouquet Head of the Humoral Immunology Unit
The Swiss army knives of the immune system
“Antibodies are veritable Swiss Army knives of the immune system,” sums up Hugo Mouquet. They are capable of neutralizing circulating viruses entering or leaving target cells, of eliminating infected cells, and of stimulating immune responses by forming complexes with viruses. To understand in detail the mode of action of broad-spectrum neutralizing antibodies, to know what makes them so effective, Hugo Mouquet and his team identify, reproduce in the laboratory and characterize these anti-HIV bNAbs in detail, one by one, since more than fifteen years now. Tedious work when you know that thousands of neutralizing antibodies circulate in the blood of elite patients, which represent approximately 1% of those infected. In other words, it is in a veritable “soup of antibodies” that researchers must find the most effective ones, those which are likely to be active once morest a majority of viral strains.
However, it is not the antibodies that the researchers will “fish for” among those circulating in the blood, but the B lymphocytes that produce them. Each isolated B lymphocyte provides access to an RNA coding for a unique antibody. The sequences coding for the antibody are then inserted into the genome of immortalized human cells which, while dividing, will produce a large number of conformal copies of this so-called “monoclonal” antibody because it comes from a single cell or clone. “When we have a sufficient quantity of monoclonal antibody, we will characterize it, establish its identity card: gene sequencing, identification of the sites of interaction with the virus, affinity for the viral envelope, structure and atomic interactions of bNAb with the envelope, or neutralizing activity in vitro and in vivo in animal models” describes Hugo Mouquet. “It should be noted that these types of scientific and methodological approaches, which began with research once morest HIV, have been adopted for other viral infections and have, for example, made it possible to very quickly generate hundreds of monoclonal antibodies once morest SARS-CoV. -2 following the start of the Covid-19 epidemic. »
Towards therapeutic antibodies
In the Virus and Immunity Unit at the Institut Pasteur, directed by Olivier Schwartz, the antiviral properties of these broad-spectrum neutralizing antibodies are also studied in vitro.
The team was thus able to describe in detail the mode of action of these antibodies once morest the viral budding that occurs on the surface of infected immune cells. “We have been working for ten years on the mechanism of action of bNAbs and were quickly able to show their effectiveness in blocking cell-to-cell transmission of the virus. More recently, in 2022, we were able to describe with Timothée Bruel, a researcher in the laboratory, that broad-spectrum neutralizing antibodies cling to viral particles and form veritable aggregates on the surface of CD4 lymphocytes”, describes Olivier Schwartz. “These aggregates therefore prevent the release of viral particles and the formation of synapses through which viruses are transmitted from cell to cell. A phenomenon of neutralization which in particular might be photographed with an exceptional level of detail in scanning electron microscopy.
The team’s researchers are also interested in the effector functions of broad-spectrum antibodies. Timothée Bruel, for example, filmed the interactions between HIV-infected T lymphocytes, neutralizing antibodies and natural killer cells (NK) using video microscopy. Images taken every five minutes show how antibodies attract and trigger the destruction of infected cells by NK cells via a process of cellular cytotoxicity. “When broad-spectrum antibodies are used, the destruction is more efficient because the NK cells establish more contact with the antibodies and the infected cell,” explains Timothée Bruel. They also studied how antibodies collaborate with another key player in the immune system, the complement system.
The antibody-virus complexes might in fact stimulate and educate the immune system, and therefore make the protective effect provided by the antibodies last.
Olivier SchwartzHead of the Virus and Immunity Unit
Antibodies: hope for vaccines?
Armed with all this knowledge, broad-spectrum neutralizing antibodies are used to explore new therapeutic approaches. In France, an ANRS-RHIVIERA clinical trial will thus begin in 2023 with the teams of Asier Sáez-Cirión and Hugo Mouquet at the Institut Pasteur in coordination with the AP-HP, to test the joint effect of a triple anti-retroviral therapy and a cocktail of two long-acting bNAbs in people newly diagnosed during the early phase of HIV infection. “The objective is to administer these antibodies early to help reduce the reservoir and promote control of the infection following stopping treatment, with the hope of achieving functional remission”, explains Hugo Mouquet. “This type of treatment can also help to assess the so-called vaccine effect of the antibodies,” emphasizes Olivier Schwartz. The antibody-virus complexes might in fact stimulate and educate the immune system, and therefore make the protective effect provided by the antibodies last. »
On the vaccine side, two major advances raised hope a decade ago. The first concerns the mode of formation of these super antibodies. Indeed, in 2013, an American team demonstrated that broad-spectrum neutralizing antibodies are sculpted over time, in response to mutations in the virus, and that they sometimes take two or three years to reach their final form and their full effectiveness. In other words, there is a co-evolution between the virus and the antibodies. “It’s a very important discovery, confirms Hugo Mouquet. In 40 years of research, no vaccine has been able to induce the production of broad-spectrum antibodies by the body. And that’s partly because we didn’t have the right instructions. Now that we know how bNAbs develop, researchers are considering vaccines that will guide the production of bNAbs, step by step, following what happens in “neutralizing elites”. »
Another aspect which explains the absence of conclusive results in terms of a vaccine: the complexity of the shape of the viral proteins. The latter, essential to stimulate the production of antibodies by the immune system, have a multitude of folds that are very difficult to reproduce in the laboratory. But in 2016, American structuralists and vaccinologists succeeded in making recombinant viral envelope proteins almost identical to those expressed on the surface of the virus. “Obtaining quasi-native antigens and having the instructions for use of broad-spectrum antibodies is the most promising strategy for developing vaccines that induce the production of bNAbs,” says Hugo Mouquet. Moreover, recent work has demonstrated for the first time the induction of effective broad-spectrum antibodies in animals thanks to this type of vaccine strategy “, he concludes.
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