Rational antibody-based HIV-1 vaccine design: current approaches and future directions

Abstract

Many antiviral vaccines elicit neutralizing antibodies as a correlate of protection. For HIV, given the huge variability of the virus, it is widely believed that the induction of a broadly neutralizing antibody (bNAb) response will be crucial in a successful vaccine against the virus. Unfortunately, despite many efforts, the development of an immunogen that elicits bNAbs remains elusive. However, recent structural studies of HIV-1 Env proteins, generation of novel bNAbs, maturation of technologies for the isolation of further antibodies, insights into the requirements for antibody-mediated protection, and novel vaccination approaches are providing grounds for renewed optimism.

Figure 1. An approach to vaccines for highly mutable pathogens

For these pathogens, e.g. HIV, classical vaccine approaches are problematic but a subset of individuals do produce the types of antibody response that, if they could be elicited by vaccination, would likely provide benefit on exposure to the pathogen. Isolation of monoclonal antibodies (mAbs) constituting these responses together with a molecular characterization of the interaction of the mAbs with their pathogen target antigens (Ag) is proposed as a route to the design of immunogens that can elicit protective responses. For HIV, Ag is the envelope spike.

Figure 2. Modeling the epitopes recognized by bNAbs onto the HIV-1 trimer

The above model is adapted from a recent cryo-electron tomographic structure of the HIV-1 trimer [28••,86]. The crystal structure of the b12-bound monomeric gp120 core has been fitted into the density map [39]. The V1/V2 and V3 loops, which are not resolved in the structure, are represented as yellow and magenta ovals, respectively. The red structure located above the trimer is representative of a human IgG1 molecule. The approximate locations of the epitopes targeted by the existing bNAbs are indicated with arrows. Carbohydrate chains are shown in blue, and the oligomannose cluster targeted by mAb 2G12 is shown in orange.