Progress in HIV-1 vaccine development

Abstract

The past 2 years have seen a number of basic and translational science advances in the quest for development of an effective HIV-1 vaccine. These advances include discovery of new envelope targets of potentially protective antibodies, demonstration that CD8(+) T cells can control HIV-1 infection, development of immunogens to overcome HIV-1 T-cell epitope diversity, identification of correlates of transmission risk in an HIV-1 efficacy trial, and mapping of the coevolution of HIV-1 founder envelope mutants in infected subjects with broad neutralizing antibodies, thereby defining broad neutralizing antibody developmental pathways. Despite these advances, a promising HIV-1 vaccine efficacy trial published in 2013 did not prevent infection, and the HIV-1 vaccine field is still years away from deployment of an effective vaccine. This review summarizes what some of the scientific advances have been, what roadblocks still remain, and what the most promising approaches are for progress in design of successful HIV-1 vaccine candidates.

Keywords: B cells; HIV-1; T cells; broadly neutralizing antibodies; vaccine.

Fig. 1

A model of the HIV-1-1 Env spike with select bnAb Fab molecules bound to bnAb sites .

Fig. 2. Comparison of Heavy Chain Mutation Frequency in HIV-1 Immunization, Influenza Immunization, and HIV-1 Broad Neutralizing Abs

Heavy chain (HC) mutation frequencies were determined for three different vaccine studies and compared to that of well-characterized bnAbs. The left two columns show HC mutation frequencies induced by two or four immunizations of a gp120 immunogen , there was a rise in mutation observed with repeated immunization. The third column shows an intermediate degree of mutation frequencies observed among antibodies isolated from the canarypox-prime Env-boost RV144 regimen in Phase II and III trials . The fourth column is the mutation frequency observed for influenza vaccine recipients ; mutation frequencies after repeated exposure to influenza are higher than those for HIV-1 vaccines. The last column shows 13 well characterized bnAbs all of which show an exceptional degree of mutation.

Fig. 3. Central deletion of B-cells expressing gp41 broadly neutralizing antibodies

Highlighted is the pre-B to immature B-cell transition, the stage of B-cell development in the bone marrow at which most B cells expressing 4E10 or 2F5 bnAbs (as BCRs) have been demonstrated in knockin mice to be profoundly impaired ^{, ,} . This stage also coincides with the first general checkpoint at which B-cell tolerance mechanisms, including apoptotic deletion, begin to occur ^, .

Fig. 4. Co-evolution of virus and a single antibody lineage in an HIV-1 seroconverter

Mature CD4+-binding site antibodies CH103-106 were isolated from circulating memory B cells at week 136 after infection. Longitudinal sampling allowed inference and reconstruction of the evolution of the infecting viral sequence and of the specific neutralizing antibody lineage. B-cell gene sequencing and bioinformatics analyses were used to infer early intermediates (IA) and the unmutated common ancestor (UCA) antibody. The left part of the figure displays a phylogenetic tree of Env sequences derived from week 4 through week 160. The UCA and IA heavy chain sequences of the CH103 antibody lineages are shown alongside viral evolution. This antibody lineage evolved to gain high-affinity Env binding, and virus neutralization evolved from strain-specific autologous virus activity to cross-reactive neutralization of heterologous viruses .