Follicular helper T cells (Tfh) are the specialized CD4 T cells for B cell help and are limiting for GCs. We propose that the features of GC biology important for developing high affinity B cells to a very difficult epitope, such as a Tier 2 nAb epitope on HIV Env trimer, are very different than the well characterized features of GC biology for conventional antigens, such as haptens or even HIV gp120 V3 loop (a non-Tier 2 neutralizing epitope) for which a very small number of mutations (1-5 aa) suffice for maturation of high affinity B cells. Major limitations in our understanding of the biology of GCs to difficult antigens include (1) Is sustained exposure to antigen in GCs necessary for the extensive somatic hypermutation (SHM) associated with the generation of bnAbs? and (2) How much sequence space is explored by GCs in response to protein immunization, and how does that compare with the SHM seen in HIV Tier 2 neutralizing Abs? We will use novel slow release technologies as tools to probe the biology of germinal centers relevant to affinity maturation against a difficult HIV trimer immunogen in non-human primates (NHP, rhesus macaques).
A broadly neutralizing antibody (bnAb)-directed HIV vaccine is possible in concept, but exceptional immunological hurdles must be overcome to reach that goal. Major limitations in our understanding of the biology of GCs to difficult antigens include (1 'Is sustained exposure to antigen in GCs necessary for the extensive somatic hypermutation (SHM) associated with the generation of bnAbs?', and (2) 'How much sequence space is explored by GCs in response to protein immunization, and how does that compare with the SHM seen in HIV Tier 2 neutralizing Abs?' We will explore these questions in the context of a candidate HIV vaccine.
