HIV-1 antibodies from infection and vaccination: insights for guiding vaccine design

Abstract

Attempts to formulate a protective HIV-1 vaccine through classic vaccine design strategies have not been successful. Elicitation of HIV-1-specific broadly neutralizing antibodies (bnAbs) at high titers that are present before exposure might be required to achieve protection. Recently, the application of new technologies has facilitated the study of clonal lineages of HIV-1 envelope (Env) antibodies, which have provided insights into HIV-1 antibody development during infection and upon vaccination. Strategies are being developed for the analysis of infection and vaccine candidate-induced antibodies, their gene usage, and their maturation pathways such that this information can be used to attempt to guide rational vaccine design.

Figure 1

Heavy complementarity determining region 3 (HCDR3) amino acid sequences of the new quaternary structure preferring conformational epitope-specific V1/V2 broadly neutralizing antibodies. The HCDR3 amino acid sequences of each of the PG9/PG16, CH01–CH04 and PGT141–PGT145 clonal lineages were obtained from GenBank deposited sequences and manually aligned. Conserved amino acids within each clonal lineage are indicated by a dot (.); deletions are indicated by a dash (–). Anionic residues (aspartic acid and glutamic acid) are bold and highlighted in yellow; tyrosine residues are inverted and highlighted in blue.

Figure 2

Steps of a B cell lineage-based approach to vaccine design. Step 1 is to isolate variable heavy (VH) and variable light (VL) chain members from the peripheral blood or tissues of patients containing broadly neutralizing antibodies (bnAbs) and to express these native Ig chain pairs as whole antibodies. Step 2 is to infer intermediate ancestor (IA) antibodies (labeled 1, 2, and 3) and the unmutated ancestor (UA) antibody. Step 3 requires producing the unmutated and intermediate ancestors as recombinant monoclonal antibodies (mAbs) and using structure-based alterations in the antigen [changes in envelope (Env) constructs predicted to enhance binding to the unmutated or intermediate ancestors] or deriving altered antigens using a suitably designed selection strategy. Vaccine administration might prime with the antigen that binds the unmutated ancestor most tightly, and this is then followed by sequential boosts with antigens optimized for binding to each intermediate ancestor. Shown here is an actual clonal lineage of the V1/V2-directed bnAbs CH01–CH04 [21]. Targeting the unmutated ancestor with an immunogen that has enhanced binding may induce higher antibody responses. If high-affinity ligands for unmutated ancestors cannot be found, then high-affinity ligands targeting the intermediate ancestors may be equally useful for triggering a response. Modified from [23] and reprinted with permission.