Germline‐targeting immunogens

Summary In 2009, Dimitrov's group reported that the inferred germline ( iGL ) forms of several HIV ‐1 broadly neutralizing antibodies ( bNA bs) did not display measurable binding to a recombinant gp140 Env protein (derived from the dual‐tropic 89.6 virus), which was efficiently recognized by the mature (somatically mutated) antibodies. At that time, a small number of bNA bs were available, but in the following years, the implementation of high‐throughput B‐cell isolation and sequencing assays and of screening methodologies facilitated the isolation of greater numbers of bNA bs from infected subjects. Using these newest bNA bs, and a wide range of diverse recombinant Envs, we and others confirmed the observations made by Dimitrov's group. The results from these studies created a paradigm shift in our collective thinking as to why recombinant Envs are ineffective in eliciting bNA bs and has led to the “germline‐targeting” immunization approach. Here we discuss this approach in detail: what has been done so far, the advantages and limitations of the current germline‐targeting immunogens and of the animal models used to test them, and we conclude with a few thoughts about future directions in this area of research.