enSHIVIG bound significantly better to gp160 or gp140 (Fig. 2d,e) than to gp120 (Fig. 2c), implying predominant binding to gp41.
These data imply that C’-ADE was predominantly due to the action of anti-gp41 antibodies present as the major fraction in enSHIVIG; other investigators have identified antibodies against the immunodominant HIV gp41 region as responsible for ADE in vitro
Thus, well characterized mAbs are unpredictable in their interactions with different HIV strains. Enhancing antibodies have also been implicated in mother-to-child transmission of HIV in a number of studies [42–44]; some reports raised the possibility that enhancement may be linked to antibodies targeting HIV-1 gp41 [
AIDS vaccine development should consider the potential of ADE-VA due to vaccine-induced antibodies during experimental vaccine trials. To rule out this possibility, passive immunization with vaccine-induced antibodies could be used as a tool in biologically relevant animal models, that is, models that reflect key aspects of HIV transmission among humans, including i) tier 2 R5 challenge viruses carrying HIV-1 Env, ii) a nonhuman primate species, and iii) antibodies that are heterologous to the challenge viruses. The latter point is important since matched homologous virus/antibody systems will exaggerate neutralization and thereby mask potential enhancement by weakly or non-neutralizing antibodies. In the realistic setting of human vaccinees’ exposure to circulating HIV strains, an exact match between immunogen composition and the myriad of HIV quasispecies can never be expected.
Indirect evidence that vaccine-induced antibodies can have adverse effects comes from a feline immunodeficiency virus (FIV) study, where cats were vaccinated with various recombinant envelope glycoproteins [46]. Although neutralization in cell-line based assays was observed in plasma samples from some vaccinated groups, no virus-neutralizing antibodies were detected in the feline lymphocyte assay. Upon FIV challenge, cell-associated FIV loads were increased in the groups vaccinated with recombinant FIV Env glycoproteins compared to other groups or controls. Passive transfer of unfractionated plasma from groups with increased cell-associated FIV enhanced viral infection parameters in the recipients. While these data imply ADE, an influence of other factor(s) present in unfractionated plasma cannot be ruled out.
In sum, AIDS virus C’-ADE is real – as our passive immunization showed significant lowering of the virus dose needed to achieve viremia indicative of ADE-VA. As such, the current study with early-stage enSHIVIG confirmed our unexpected finding with late-stage SHIVIG, selected for maximal in-vitro tier 2 SHIV cross-neutralization, where low-dose pretreatment yielded sub-neutralizing anti-HIV Env IgG levels that significantly increased the number of transmitted viral quasispecies. Together, our data imply that decreasing anti-HIV Env neutralizing antibody titers could bring vaccinated individuals into a situation where ADE-VA prevails.
ADE-VA may be of concern for other pathogens, especially rapidly mutating RNA viruses susceptible to neutralization escape. Vaccine development will need to consider potential enhancement of host susceptibility to infection due to ADE [47,48]. We propose that our strategy – passive immunization with purified polyclonal IgG isolated from previously infected/vaccinated individuals, combined with in-vivo end-point virus titration to assess the amount of virus needed to achieve infection of naïve versus passively immunized animals, can play an important role in assessing the potential for ADE-VA.
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