Fine-mapping HIV-1 antibody responses to guide vaccine design

The development of a vaccine will be essential to combat, control and eventually eradicate the human immunodeficiency virus (HIV-1) from the human population. Nearly all viral vaccines work through the induction of antibodies in serum or mucosa that neutralize the pathogen before it can establish an infection. The envelope glycoprotein (Env) of HIV-1 is the only viral component on the surface of the virus and thus the sole target for neutralizing antibodies (NAbs). The development of Env-specific broadly neutralizing antibodies (bNAbs) in a subset of HIV-1 infected individuals has demonstrated that humans can produce potent, cross-neutralizing antibodies after years of infection. However, no HIV-1 vaccine has been able to elicit such responses to date. In the last two decades, the advances in immunology and structural biology have revolutionized vaccine development, allowing the (structural) characterization of isolated monoclonal antibodies (mAbs) in complex with their cognate antigen to improve the immunogenicity and effectiveness of vaccine candidates. In this thesis, we exploited structure-based reverse vaccinology to gain insight into the molecular mechanisms behind HIV-1 Env vaccine-, and infection-induced antibody responses to improve current vaccine candidates. In the first part, we present our work that explains the absence of strong neutralization breadth in non-human primates immunized with native-like trimers derived from various HIV-1 env sequences. In the second part of the thesis, we studied the antibody-virus co-evolution in an HIV-1 infected elite neutralizer, and revealed the molecular mechanisms underlying the extraordinary serum breadth of this individual.