Background: Induction of bnAbs remains a critical goal towards developing a vaccine against HIV-1. We previously grafted 4E10 epitope of HIV-1 gp41 on the surface of human rhinovirus connected via linkers of varying lengths and sequences to construct combinatorial HRV display libraries. One chimeric HRV:HIV immunoselected from the libraries was able to elicit broad neutralization against 10 of 12 HIV-1 pseudoviruses in guinea pigs. However, guinea pigs do not get infected with HRV because they lack the viral receptor, human ICAM-1 and thus the antibody titers were rather modest. Since the recently developed hICAM-1 Tg mice support productive HRV infection, in this study we evaluated the efficacy of chimeric HRV:HIV vaccine in these mice.
Methods: hICAM Tg mice were intranasally immunized with three representative chimeric HRV:HIV viruses chosen from our previous study. The sera collected at different time points were tested for immunogenicity and HIV neutralization. ELISA was used to test the binding affinity against 4E10 peptide as well as HIV-1 gp140 trimer. The neutralizing ability against HIV-1 isolates was tested by single-round Tat-regulated luciferase assay in TZM-bl cells. Also, 11 HIV-1 internationally circulating isolates of diverse subtypes and coreceptor usages were used to test the breadth of neutralizing ability. HRV pre-immunized Tg mice were further immunized with chimeric HRV:HIV to test whether nasal administration can bypass HRV pre-immunity.
Results: The sera from the immunized mice showed good binding affinity with 4E10 peptide as well as with HIV-1 gp140 trimer. All three chimeric HRV:HIV elicited neutralizing antibody responses in hICAM-1 Tg mice against diverse isolates of HIV-1, with one eliciting anti-HIV antibodies capable of neutralizing 9 of the 11 internationally circulating HIV-1 isolates at IC50 level (from six subtypes and two co-receptor usages of HIV-1). Furthermore, intranasal administration of chimeric HRV:HIV could bypass the preexisting immunity to HRV to elicit anti-HIV response.
Conclusions: This work demonstrates that productive infection of HRV susceptible animals with chimeric HRV effectively elicits broadly neutralizing anti-HIV-1 antibodies. This strategy therefore appears to have potential for human vaccination.