A Blueprint for HIV Vaccine Discovery

Abstract

Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine.

Figure 1. Structure and antibody recognition of the HIV Envelope spike

The molecule is a heterotrimer of composition (gp120)3 (gp41)3. Gp41 is a transmembrane protein and gp120 is the receptor molecule for CD4 and CCR5 (or CXCR4). The model is adapted from a cryo-electron tomographic structure of the HIV trimer (Liu et al., 2008). The crystal structure of the b12-bound monomeric gp120 core (red) has been fitted into the density map (Zhou et al., 2007). Glycans are shown in purple. The CD4 binding site is shown in yellow. The approximate locations of the epitopes targeted by existing bnMAbs are indicated with arrows, and the number of MAbs targeting each epitope is shown in red boxes. A small selection of bnMAbs targeting each epitope is included.

Figure 2. The evolving definition of broad and potent neutralization of HIV

For a long period, MAbs such as b12, 2G12 and 4E10 were the most potent and broad available. MAbs PG9 (Walker et al., 2009) and VRC01 (Wu et al., 2010) were discovered and shown to be broad and about an order of magnitude more potent. Later, MAbs PGT121 and PGT128 (Walker et al., 2011a) were shown to be even more potent. The engineered MAb NIH45-46^G54W is still more potent and broad (Diskin et al., 2011). Enhanced neutralization potency, if translated into enhanced protective ability, is important since it reduces the level of antibody that should be induced by a vaccine.

Figure 3. Model for native Env glycosylation

Following removal of terminal α-linked glucose residues in the endoplasmic reticulum (ER), folded glycoproteins contain exclusively oligomannose glycans. During transit through the ER, intermediate compartment and cis-Golgi apparatus, Manα1-2Man termini are removed by mannosidases to yield Man5GlcNAc2. However, the oligomannose cluster intrinsic to monomeric gp120 limits glycan processing on both monomeric and oligomeric gp120. The steric consequences of trimerization further limit Manα1-2Man trimming leading to an additional ‘trimer-associated’ population of Man5–9GlcNAc2. The exposed Man5GlcNAc2 glycans on gp120 that passage through the full extent of the Golgi apparatus and trans Golgi network to the plasma membrane are processed to form complex-type glycans. However, envelope glycoprotein that does not follow this route to the plasma membrane- a notable feature of some pseudoviral production systems- is characterized by an elevated abundance of Man5GlcNAc2 and reduced furin cleavage (Crooks et al., 2011). Thus the intrinsic mannose patch, which includes the 2G12 epitope, persists from the earliest stages of glycan processing whilst other elements of the glycan shield exhibit variably processed glycans depending on oligomerization state and, at least in the case of pseudoviral gp160/gp120, cellular trafficking (adapted from (Bonomelli et al., 2011).

Figure 4. T follicular helper (Tfh) cells are the CD4+ T cells that are required for germinal centers (GC) and control B cell differentiation within the GCs

Tfh cells provide different signals to B cells to control different B cell fates, such as plasma cell (antibody secreting cell) differentiation, memory B cell differentiation, death, or repeated rounds of somatic hypermutation and GC B cell proliferation. Generation of high-affinity neutralizing antibodies is generally a multi-step, iterative process that is dependent on affinity maturation via somatic hypermutation and extensive signaling from Tfh cells (Crotty, 2011).

Figure 5. An approach to HIV vaccine discovery

Molecular data on protective Abs (typically bnAbs), Env and Ab-Env complexes, should facilitate the generation of antigens presenting protective epitopes. These antigens can then be formulated as immunogens and tested in animals and humans. The characteristics of the protective Abs also provide information on how they were generated that can be investigated in B and CD4+ T cell studies, guiding both immunogen design and immunization strategies. Gaps in our current knowledge suggest that iteration will be an important part of the development of vaccine candidates as indicated by the feedback loops shown in the figure.