Selecting HIV-1 neutralizing mAbs from Californian donors
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Some HIV+ patients develop virus-fighting molecules in their blood called antibodies. These antibodies are highly significant for research into an AIDS vaccine and may provide new therapeutic options for infected patients. However, despite the enormous efforts of researchers, only very few have been isolated. Here, we will combine two powerful approaches to try to isolate new virus-fighting antibodies. Problem 1: Virus-fighting antibodies are extremely rare, and the challenge to isolate them might be likened to "finding a needle in a haystack". A method to enrich them would be useful. Solution 1: As a resource, we will use libraries of antibodies prepared from HIV patients that are displayed on the surfaces of a pencil-like viruses. The pencil-like virus scaffold to which the antibodies are attached also contain the identification tags (DNA) of the antibody. Literally like books on library shelves, these libraries reflect the diverse swarm of about a million antibodies in the patient donor. Although each library may be packed with "cheap bestsellers", it should be of sufficient diversity to contain a "Pulitzer prize winner". Selection occurs when rare books from the library are chosen, others discarded, and replaced by multiple copies of the rare book(s), which can then be easily retrieved. Problem 2: In the past, researchers have generally used fragments of virus particles to select out antibodies. While easier to work with, these attempts have been, at best, only partially successful. The problem may be inappropriate selection criteria. Solution 2: If the right selection criteria can be found, it is possible that the "rare books" can be accessed. Since only whole virus particles bear the targets known to distinguish the "good" from the "bad" books, we will search our libraries using whole virus particles. We will also try to focus the selection on the right part of the virus. In practice, we realize that the selection criteria must be perfected if we are to have a chance of isolating the rare "prize winner". Therefore, we will initially optimize the selection procedure using simplified libraries of only two "books". In this method, one previously identified "prize winner" is a virus-fighting antibody and the other has no activity against the virus. In a straightforward procedure, we will evaluate various ways to select the "prize winner" over the other. Once a procedure is in place to select the "rare book" 100 times favored over the other, we will try to select new "Pulitzer prize winners" from whole libraries of more than a million "books" prepared from Californian HIV+ patients. Just as different libraries might have different inventories of books, so do the libraries of antibodies from different HIV+ patients. Therefore, checking the libraries of several patients should maximize our chances of retrieving a "rare edition". This would be an enormous breakthrough for the field, and the first significant new addition to a collection of only 4 virus-fighting antibodies isolated more than a decade ago, despite the best efforts of researchers. Should we succeed, we will have some very exciting preliminary data to enable us to apply for government grant funding. Our long-term goal is to understand how patient antibodies wipe out HIV, and to harness this information to advance HIV vaccine research.