Human Immunodeficiency Virus (HIV) has always remained havoc for the whole human population. The scientists are eager to come up with a new invention which can completely eradicate HIV AIDS from our environment. Among all their earlier researches, vaccination against the HIV virus has always been the hot topic of research for the researchers and scientists. The scientists are trying to design a vaccine which can stimulate the immune system to produce the right kind of antibody response to protect against a wide range of viral strains. This new technique was illustrated by the scientists by engineering an immunogen that can probably initiate an effective response against many types of HIV. These immunogens would be primarily tested on the mice engineered to produce human antibodies and then eventually in the humans.

The viruses such as HIV and influenza are highly variable in nature. The researchers want to elicit antibodies that can guard us not only from few strains, like seasonal flu vaccines but against most or all viral strains. They have identified several of these broadly neutralizing antibodies from long-term HIV-positive survivors, harvesting antibody-producing B cells from blood samples and then sifting through them to identify those that produce antibodies capable of neutralizing multiple strains of HIV. Such broadly neutralizing antibodies typically work by blocking crucial functional sites on a virus that are conserved among different strains despite high mutation elsewhere.

Though, we have powerful broadly neutralizing antibodies with us, but the scientists are still trying hard to find a way to elicit their production in the human body through a vaccine. For introducing the broadly neutralizing VRC01-class antibodies which can neutralize 90 percent of the known HIV strains, the HIV envelope protein can be used as our immunogen. But still the problem persists as the envelope protein doesn't bind with any detectable affinity to the B cells which is required to launch a broadly neutralizing antibody response. The scientists evaluated the genes of VRC01-producing B cells to deduce the identities of the less mature B cells which are known as germline B cells. Germline B cells are the major targets of the viral vaccines, because it is the initial stimulation of these B cells and their antibodies that might lead to a long-term antibody response. In response to the ]vaccination, these germline B cells could mature into the desired VRC01-producing B cells but the natural HIV proteins fail to bind or stimulate these germline B cells so they cannot get the process started. The researchers thus set out to design an artificial immunogen that would be successful at hitting the target. the scientists used a protein modeling software to improve the binding of VRC01 germline B cell antibodies to the envelope protein of HIV. This software can recognize dozens of mutations that could help in improving the binding to the germline antibodies. Through this software large number of libraries were generated that contained all possible combinations of beneficial mutations, resulting in millions of mutants, and screened them using techniques called yeast surface display and FACS. This combination of computational prediction and directed evolution successfully produced a few mutant envelope proteins with high affinity for germline VRC01-class antibodies. the Engineered Outer Domain (eOD) was used by the researcher team to develop an immunogen much smaller than HIV envelope. After several repetitive rounds of design and selection using a panel of germline antibodies, an optimized immunogen was developed finally. They named it as eOD-GT6.

To understand and study the 3D structure of the immunogen, the researchers determined the 3D atomic structure of the designed immunogen using X-ray crystallography (XRC). This helped in the estimation of the crystal structure of a germline VRC01 antibody and the structure of the immunogen and antibody bound together. Thus, eOD-GT6 achieved success in its mechanism and its binding to the antibody.

The researchers wanted the immunogen to look like a virus as it is better at stimulating an antibody response when it is presented as a closely spaced cluster of multiple copies, and with only its antibody-binding end exposed. So, a tiny virus-copying particle was devised from some 60 copies of an obscure bacterial enzyme and coated it with 60 copies of eOD-GT6. The particle worked well at activating VRC01 germline B cells and even matures B cells in the lab dish, whereas single-copy eOD-GT6 did not.

The self-assembling nanoparticle presented an immunogen in a properly oriented manner. This approach can be used not just for designing the vaccine of an HIV virus but for developing the vaccines of many other viruses as well. Now, the next venture is to test that whether it has the ability to stimulate an antibody response in-vitro in the laboratory animals that are themselves engineered to produce human germline antibodies. The sole difficulty with testing immunogens that target human germline antibodies is that animals typically used for vaccine testing cannot make those similar antibodies. We could just hope that sooner the researchers would discover to drive the response from the activation of the germline B cells all the way to the production of mature and broadly neutralizing VRC01-class antibodies using a series of designed immunogens. This would be launched in the market after all the phases of clinical trials on human beings and FDA approval.

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Geetanjali Murari
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