Neutralizing antibody and T cell based immunogen design strategies. In this schematic, some immunogen design strategies discussed in this review are highlighted. A) A virus-like particles (VLP) from which non-functional Env have been removed from the surface by enzymatic digestion is shown. Gp120 and gp41 native trimers are represented in green and pink respectively. B) A native stabilised soluble envelope trimer is shown. Current strategies for stabilisation include mutation of the gp120-gp41 cleavage site, introduction of trimerisation domains, introduction of disulphide bonds between gp120 and gp41, and gp41 trimer stabilising mutations. The modifications (represented by black solid lines) may enhance solubility, reduce aggregation or expose neutralizing antibody epitopes. C) Stabilization of neutralizing antibody epitopes- represented by the red, blue and yellow ovals- on a molecular scaffold (grey) after they have been identified by mutagenesis and computational approaches. D) Mosaic immunogens comprise a small number of protein sequences from various HIV proteins and are created using computational approaches from recombination of naturally-occurring protein sequences in a given viral population. They are designed to achieve maximal coverage of natural variation of all potential T cell epitope sequences in a particular viral population. E) T cell epitopes and conserved elements are identified and used to construct an immunogen which may also require optimisation for expression, processing and antigen presentation. F) Immunogens designed to impact on viral fitness and prevent viral immune escape. In this approach, immune responses are targeted at epitopes in which escape results in significant fitness cost on the virus, or target compensatory mutations (both depicted by a red crosses). The virus is thus suppressed by effective T cell immune responses or becomes attenuated following escape. The attenuated virus has very low in vivo fitness (shown by the red line) and cannot be transmitted or cause disease following acute HIV infection (grew window). The grey broken line represents a hypothetical fitness threshold that would need to be achieved for this strategy to work.