Structure-Based Reverse Vaccinology Failed in the Case of HIV Because it Disregarded Accepted Immunological Theory
- Marc H. V. Van Regenmortel
- International journal of molecular sciences
INTRODUCTION Human Immunodeficiency Virus-1 (HIV1) presents profound challenges to vaccine developers. Potential hurdles of relevance to the design of an effective HIV-1 vaccine based on humoral immunity include: (1) the exceptional rate of mutation of the viral genome due to an error-prone polymerase (i.e., reverse transcriptase) (1), (2) a relatively high rate of genomic recombination (2, 3), (3) both within-host and between-host evolution (4), (4) extensive glycosylation of the chief antigenic target (gp120) recognized by potentially protective antibodies (5, 6), (5) immunodominance of regions of the envelope glycoprotein that display a high degree of primary structure diversity (7) favoring the generation of neutralizing antibodies of narrow breadth, (6) a relatively low density of antigen spikes on the virion surface (8, 9) thereby minimizing multivalent antibody binding and perhaps raising the threshold affinity required for potent neutralization by at least some antibodies, (7) the ability of HIV to infect CD4 T cells and other cells critical to functioning of the immune system, and deplete the numbers of these cells, and (8) perhaps most insidious, activation of CD4 T cells, which is necessary for the generation of potent broadly neutralizing antibodies in response to immunization may simultaneously increase the number of cells susceptible to infection by HIV (10, 11). The scale of the antigenic diversity characterizing the HIV-1 envelope molecules, which are the primary targets of antibodymediated immunity, is truly daunting. According to Korber et al. (1), the HIV-1 viral genomes in one infected individual encompass the same approximate extent of nucleotide sequence diversity that is exhibited by the worldwide population of influenza A viral genomes over the course of a year. While most HIV transmission events appear to trace back to a single virus, up to a quarter of infections may involve infection by two to five viruses (12). So, even if vaccine immunization elicits a robust antibody response, the probability that the antibodies circulating in the blood of a vaccinated individual will effectively neutralize or otherwise mediate immunity against all of the viruses mediating infection will be greatest if those antibodies are broadly neutralizing. In addition, due to rapid within-host evolution, substantially different viruses may be infecting different individuals in a large population. Therefore, antibodies generated by vaccination will need to be broadly neutralizing to achieve high levels of vaccine efficacy.