Abstract
BackgroundThe development of an HIV/AIDS vaccine has proven to be elusive. Because human vaccine trials have not yet demonstrated efficacy, new vaccine strategies are needed for the HIV vaccine pipeline. We have been developing a new HIV vaccine platform using a live enterovirus, coxsackievirus B4 (CVB4) vector. Enteroviruses are ideal candidates for development as a vaccine vector for oral delivery, because these viruses normally enter the body via the oral route and survive the acidic environment of the stomach.Methodology/Principal FindingsWe constructed a live coxsackievirus B4 recombinant, CVB4/p24(733), that expresses seventy-three amino acids of the gag p24 sequence (HXB2) and assessed T cell responses after immunization of mice. The CVB4 recombinant was physically stable, replication-competent, and genetically stable. Oral or intraperitoneal immunization with the recombinant resulted in strong systemic gag p24-specific T cell responses as determined by the IFN-γ ELISPOT assay and by multiparameter flow cytometry. Oral immunization with CVB4/p24(733) resulted in a short-lived, localized infection of the gut without systemic spread. Because coxsackieviruses are ubiquitous in the human population, we also evaluated whether the recombinant was able to induce gag p24-specific T cell responses in mice pre-immunized with the CVB4 vector. We showed that oral immunization with CVB4/p24(733) induced gag p24-specific immune responses in vector-immune mice.Conclusions/SignificanceThe CVB4/p24(733) recombinant retained the physical and biological characteristics of the parental CVB4 vector. Oral immunization with the CVB4 recombinant was safe and resulted in the induction of systemic HIV-specific T cell responses. Furthermore, pre-existing vector immunity did not preclude the development of gag p24-specific T cell responses. As the search continues for new vaccine strategies, the present study suggests that live CVB4/HIV recombinants are potential new vaccine candidates for HIV.
Highlights
The development of an HIV/AIDS vaccine has proven to be elusive in spite of research efforts spanning over a quarter century [1,2,3]
Because a longer coxsackievirus B4 (CVB4) genome could alter the physical packaging of RNA and capsid proteins, thereby affecting viral stability, we evaluated the physical stability of the recombinant
The CVB4/p24(733) recombinant was designed to express the gag p24 sequence as an intracellular, non-structural peptide which would be processed through the MHC class I pathway, thereby allowing presentation of the p24 CTL peptide to CD8 T cells
Summary
The development of an HIV/AIDS vaccine has proven to be elusive in spite of research efforts spanning over a quarter century [1,2,3]. Because human vaccine trials have not yet demonstrated efficacy [7,8,9,10], new vaccine strategies are needed for the HIV pipeline. Because HIV infection is a disease of the mucosal immune system with systemic manifestations [11,12,13], new vaccine approaches must induce both mucosal and systemic T and B cell responses. One approach to induce immunity in the gastrointestinal mucosa is by oral delivery of suitable vaccines. A well-known example of an effective vaccine capable of inducing immune responses in the gastrointestinal mucosa and in the systemic circulation after oral delivery, is the live attenuated Sabin vaccine for poliomyelitis [14]. Enteroviruses are ideal candidates for development as a vaccine vector for oral delivery, because these viruses normally enter the body via the oral route and survive the acidic environment of the stomach
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