Abstract
The global health burden engendered by human immunodeficiency virus (HIV)-induced acquired immunodeficiency syndrome (AIDS) is a sobering reminder of the pressing need for a preventative vaccine. In non-human primate models replicating adenovirus (Ad)-HIV/SIV recombinant vaccine vectors have been shown to stimulate potent immune responses culminating in protection against challenge exposures. Nonetheless, an increase in the transgene carrying capacity of these Ad vectors, currently limited to approximately 3000 base pairs, would greatly enhance their utility. Using a replicating, E3-deleted Ad type 5 host range mutant (Ad5 hr) encoding full-length single-chain HIVBaLgp120 linked to the D1 and D2 domains of rhesus macaque CD4 (rhFLSC) we systematically deleted the genes encoding early region 4 open reading frame 1 (E4orf1) through E4orf4. All the Ad-rhFLSC vectors produced similar levels of viral progeny. Cell cycle analysis of infected human and monkey cells revealed no differences in virus-host interaction. The parental and E4-deleted viruses expressed comparable levels of the transgene with kinetics similar to Ad late proteins. Similar levels of cellular immune responses and transgene-specific antibodies were elicited in vaccinated mice. However, differences in recognition of Ad proteins and induced antibody subtypes were observed, suggesting that the E4 gene products might modulate antibody responses by as yet unknown mechanisms. In short, we have improved the transgene carrying capacity by one thousand base pairs while preserving the replicability, levels of transgene expression, and immunogenicity critical to these vaccine vectors. This additional space allows for flexibility in vaccine design that could not be obtained with the current vector and as such should facilitate the goal of improving vaccine efficacy. To the best of our knowledge, this is the first report describing the effects of these E4 deletions on transgene expression and immunogenicity in a replicating Ad vector.
Highlights
Vaccines are essential tools in the global effort to reduce deaths due to multiple diseases
The results of this study provide evidence that while deletion of early region 4 open reading frame 1 (E4orf1) through E4orf4 expands the transgene carrying capacity of replicating Ad vectors, these deletions have little to no effect on virus-host cell interaction, transgene expression, T-cell immunogenicity, or transgene-specific antibody binding titers
Replicating Ad is currently being developed as a delivery vector for use in both human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and influenza vaccines, its 3kb carrying capacity limits the size of the transgene that can be inserted
Summary
Vaccines are essential tools in the global effort to reduce deaths due to multiple diseases. Successful vaccines have been developed against the proverbial ‘‘low hanging fruit;’’ the continued lack of effective vaccines against diseases such as malaria, tuberculosis, and HIV/AIDS underscores the need for even greater efforts aimed at the design and development of preventative vaccines. As part of a preventative HIV vaccine strategy, it has been shown to elicit potent humoral and cellular immune responses [1]. Most importantly for HIV, the replicating Ad vaccine vector targets and persists at mucosal sites [2] where HIV makes its initial entry [3]. Today, replicating Ad sub-type 4 (Ad4DE3) is being developed as a delivery vector for both HIV/AIDS and influenza vaccines [11,12]
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