Antibodies in HIV-1 vaccine development and therapy

Abstract

Despite 30 years of study, there is no HIV-1 vaccine and, until recently, there was little hope for a protective immunization. Renewed optimism in this area of research comes in part from the results of a recent vaccine trial and the use of single-cell antibody-cloning techniques that uncovered naturally arising, broad and potent HIV-1-neutralizing antibodies (bNAbs). These antibodies can protect against infection and suppress established HIV-1 infection in animal models. The finding that these antibodies develop in a fraction of infected individuals supports the idea that new approaches to vaccination might be developed by adapting the natural immune strategies or by structure-based immunogen design. Moreover, the success of passive immunotherapy in small-animal models suggests that bNAbs may become a valuable addition to the armamentarium of drugs that work against HIV-1.

Figure 1. Antibody target sites on the HIV-1 envelope spike

Schematic representation of the HIV-1 envelope spike. Each of the monomer units of the trimer is composed of a gp120 (blue) and gp41 transmembrane protein (grey). The four best-characterized broadly neutralizing target sites are highlighted and include the CD4 binding site (orange); the glycan-associated epitopes on the base of the V3 loop (purple); the V1/V2 loop (green); and the MPER on gp41 (grey). EM-derived illustration of the envelope spike targeted by representative broadly neutralizing F(ab)s shown approximately to scale (bottom; NIH45–46, yellow; PG16, green; PGT128, purple; 2F5, grey). Examples of first- and second-generation bNAbs that target these and other sites are color-coded and indicated at the right hand side.

Figure 2. The HIV-1 envelope-specific B cell response

Naïve B cells selected by antigen interact with cognate T cells and are recruited to the germinal center. In the dark zone (DZ) B cells proliferate and express Activation-induced deaminase (AID) resulting in the acquisition of somatic mutations. The cells of this expanded and diversified B cell clone migrate to the light zone (LZ) where they encounter the antigen (e.g. viral envelope protein; dark green) presented as immune complexes on the surface of follicular dendritic cells. High affinity antigen-binding B cells that capture and present antigen to T cells are selected to return to the dark zone to proliferate or differentiate into memory B or plasma cells. High affinity envelope-directed antibodies produced by the plasma cells exert selection pressure on the virus population, but viral escape variants emerge and expand (light green). Envelope antigens expressed by the selected virus clone are presented to either naive B cells or to memory B cells that have already encountered an HIV-1 envelope antigen thereby re-initiating the cycle of clonal selection and somatic mutation.

Figure 3. Implications for vaccine design by studying HIV-1 and antibody co-evolution in an individual with bNAbs

Longitudinal analysis of an HIV-1-infected individual was performed from the time of infection up to the development of bNAbs (Liao et al., 2013). The evolution of the HIV-1 envelope on the virus drives the diversification of the antibody response. Isolation and sequences analysis of the HIV-1 envelope on the founder virus (red square) and on viruses at later stages (green to dark green) provides crucial information for generation of antigens that can potentially elicit a broadly neutralizing antibody response. Mimicking the evolution of antigens in an HIV-1 vaccine approach is a promising strategy to elicit bNAbs in humans.

Figure 4. Potential use of bNAbs in HIV-1 therapy

Suggested settings for the evaluation of bNAbs in clinical trials. A.) Different modes of action in anti-retroviral drugs (ART) and HIV-1 neutralizing antibodies might result in significant HIV-1 treatment intensification in humans. B.) Prevention of viral rebound while ART is halted might be accomplished by HIV-1 antibody therapy. In order to reduce the likelihood of viral escapes from bNAbs, HIV-1-infected individuals should have fully suppressed viral loads before antibody therapy is started. C.) Treatment with a combination of bNAbs could be of particular interest, especially if individuals either do not tolerate (e.g. drug-drug interaction, severe side-effects) ART or are resistant to it.