Molecular characterization of the HIV-1 N332 epitope-cluster
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: By inflicting the acquired immune deficiency syndrome (AIDS) the human immunodeficiency virus (HIV) has claimed about 25 million lives over the past three decades. While over time the virus has become more manageable through the development of highly effective drugs, less than 25% of the 34 million people living with HIV today (as of 2011) are actually being treated for various reasons - as a consequence, about 2.5 million people still get newly infected with the virus every year. To counter-act the untamed spread of the virus, researchers have been seeking to create an HIV vaccine ever since the relation between HIV and AIDS has been established. The general idea of vaccination is to alert the human body’s own defenses, the immune system, by challenging it with a safe substance, the vaccine or immunogen, which mimics the actual virus in its molecular characteristics. In response, the immune system elicits specifically tailored proteins called antibodies that ideally bind and neutralize the immunogen as well as the real virus upon infection. In the case of HIV, the only target accessible to the immune system is the envelope protein (Env), which is comprised of two subunits gp120 and gp41. These subunits form a trimer of dimers on the viral surface, the Env spike, which the virus uses to dock onto and infect immune cells. Hence, all vaccination efforts aimed at inducing anti-HIV neutralizing antibodies mainly focused on various forms of trimeric Env, gp120 or gp41 to induce protective immunity against HIV. Unfortunately, no vaccine trial in the past 25 years has been successful at protecting individuals against the vast array of circulating viral strains. The reasons for that, while diverse and in part not well understood, are foremost the very high mutation rate of the virus, which continuously alters the target presented to the immune system and the dense attachment of sugars - so called glycans - to gp120 and gp41, which disguises these proteins and makes them appear less dangerous, thus misleading the immune system. Hopes for a universal vaccine were recently reinvigorated with discovery of broadly neutralizing antibodies (bNAbs) in some long term infected HIV patients. These antibodies have the ability to neutralize up to 90% of all known circulating HIV strains, taking away the mutational edge the virus has in its arms race against the immune system. BNAbs are known to bind four distinct areas, so called epitopes, on gp120 and gp41, the most potent of which attack the N332 epitope cluster on gp120. Only few such bNAbs are known and thoroughly characterized to date. To enable the design of immunogens mimicking the most broadly and potently neutralized areas of the N332 epitope cluster, my research aims at i) isolating novel bNAbs from a small panel of long term infected donors with variously broad and potent blood serum responses against the epitopes in question and to ii) biochemically as well as iii) structurally characterize these antibodies and their binding sites. Ideally, the insights gained from this study can make specific and detailed suggestions as to what parts of gp120 vaccine candidates need to resemble in order to present a easy-to-recognize target to the immune system, which in turn could induce a focused, potent and broadly neutralizing immune response, potentially protecting from HIV infection. Additionally, bNAbs have recently been investigated as treatment and prevention alternatives, by passive administration.