Production and characterization of novel immunogens and their applications in pioneering vaccination strategies for induction of broadly neutralizing antibodies against HIV-1

Abstract

<p>Though estimates vary, approximately 80 million people have been infected with HIV-1 and ~40 million have been killed as a result since it's discovery as the cause of AIDS in 1984. The total number of cases is unknown and believed to date back to an original transmission between chimpanzees and humans sometime between 1900 and the 1920's in Kinshasa, Democratic Republic of Congo. Despite decades of research the HIV epidemic has continued without the development of an effective cure or vaccine. As eradication of the virus will likely require a combination of prophylactic and treatment methods, development of an effective vaccine remains a priority. The modestly efficacious RV144 trial has shown that vaccination can have an effect on viral infectivity and that pursuit of this route of inhibiting viral spread is critical in the fight against HIV-1. Unfortunately, this trial failed to elicit broad neutralization against multiple viral strains. Over the years a number of vulnerable sites on the viral envelope have been identified in conjunction with the broadly neutralizing antibodies (bnAbs) that bind them. The membrane proximal external region (MPER) as well as the CD4 binding site have been recognized as the targets of some of the most potent bnAbs. Many novel vaccination strategies have demonstrated the importance of how epitopes are presented and how we can manipulate target regions to enhance immunogenicity. Our work has enhanced the understanding of the MPER and CD4 binding site as neutralizing epitopes by evaluating multiple immunogens and immunization strategies. These studies shed light on the role of epitope presentation in vaccines as well as how antibodies stabilize epitope conformations for immune presentation.</p>