Structure-based design of HIV-1 immunogens

Project Abstract

The HIV-1 vaccine field has gone through several significant paradigm shifts, with recent years seeing an overwhelming push toward “rational” immunogen design that incorporates information about known broadly neutralizing antibodies (bNAbs), their epitopes on HIV-1 Env, and the bNAb-epitope interactions. Yet, no current immunogens have been able to elicit bNAb responses in pre-clinical or clinical trials. However, the use of improved trimeric soluble immunogens, such as the prototypic BG505.SOSIP and its derivatives, have resulted in some autologous Tier 2 neutralization in rabbits and, to a lesser extent, non-human primates. These results suggest that the HIV vaccine field may be close to the design of a broadly protective vaccine, but the question remains open: How do we take the next steps that would be necessary for the successful design of such a vaccine? Here, we propose to apply structure-based protein design techniques in order to develop novel HIV-1 immunogens with focused epitope specificity and improved stability. Immunogen candidates will be produced and experimentally validated using a variety of assays, including negative-stain EM and B-cell activation. Top candidates will be used for immunization in animal models.

Training Plan

Clint Holt’s project is a computational vaccine design project that will benefit immensely from mentorship in both the computational and experimental aspect of the work. The primary faculty mentor, Dr. Georgiev, is a computational immunologist and virologist. Dr. Georgiev has had extensive experience with computational protein design and vaccine engineering, including for HIV-1. Dr. Georgiev will train Mr. Holt and will oversee algorithm development and testing, as well as data generation, analysis, and reporting. The secondary faculty mentor, Dr. Crowe, is an immunologist and virologist with extensive experience in antibody generation and characterization, including for HIV-1. Dr. Crowe will be Mr. Holt’s mentor on the biological side of the project. Dr. Crowe will provide insights into the specifics of the human antibody response to HIV-1 immunization, that will allow to make the computational modeling as close to realistic as possible. Overall, the combined expertise of Dr. Georgiev and Dr. Crowe will be an excellent fit for the goals of Mr. Holt’s project, and will enable the development of an important new technological advance that will help provide new templates for rational vaccine design against HIV-1.

Mentors

Primary: Ivelin Georgiev

Secondary: James Crowe Jr.