Critical design criteria for engineering a nanoparticulate HIV-1 vaccine.

Inducing a long-lasting as well as broad and potent immune response by generating broadly neutralizing antibodies is a major goal and at the same time the main challenge of preventive HIV-1 vaccine design. Immunization with soluble, stabilized and native-like envelope (Env) glycoprotein so far only led to low neutralization breadth and displayed low immunogenicity. A promising approach to generate a potent immune response is the presentation of Env on the surface of nanoparticles. In this review, we will focus on two key processes essential for the induction of immune response that can be addressed by specific features of nanoparticulate carriers: first, the trafficking to and within distinct compartments of the lymph node, and second, the use of multivalent Env display allowing for high avidity interactions. To optimize these pivotal steps critical design criteria should be considered for the presentation of Env on nanoparticles. These include an optimal particle size below 100 nm, distances between two adjacent Env antigens of approximately 10-15 nm, an appropriate orientation of Env, and finally, the stability of both the Env attachment and the nanoparticle platform. Hence, an interdisciplinary approach that combines a suitable delivery system and a straightforward presentation of the Env antigen may have the potential to drive the immune response towards increased breadth and potency.