(162e) Design of Components and Protocols for Inducing Protective Antibodies Against HIV

No universal vaccines exist for infectious diseases like HIV, flu, and malaria partly because of the high genetic variability of the pathogens that cause these diseases. Vaccination strategies aimed at targeting conserved regions of the pathogenic machinery could mount broadly-neutralizing immune responses, potentially leading to the global eradication of such diseases through a single universal vaccine. Broadly-neutralizing antibodies (bNAbs) have now been isolated from patients with HIV, flu, and malaria that bind to conserved regions on pathogenic proteins called antigens (Ags), and are able to neutralize many different strains of the pathogen. However, the vaccine formulation and administration methods required to optimally promote bNAb formation remains unclear. Through the study of a wide range of possible immunization schemes, this talk will showcase the use of two computational approaches with increasing resolution and biological relevance for studying the development of bNAbs against highly mutable pathogens such as HIV. Results from a heavily coarse-grained model of antibody evolution in a germinal center reaction (GCR) show optimal temporal patterns of administration exist to promote bNAb formation. These optimal temporal immunization schemes can be determined using a predictive framework that has been developed from governing, empirically-determined scaling laws. Results from a more realistic model, focused on studying the sequence evolution and binding of VRC01-like bNAbs to the CD4 binding site of HIV GP120, show that optimal Ags also exist that promote bNAb formation. A two-step, lock-and-key-like mechanism is proposed for bNAb binding to the CD4 binding site.