RESUMO
Sindbis replicon-based vaccine vectors are designed to combine the immunostimulatory properties of replicating viruses with the superior safety profile of non-replicating systems. In this study we performed a detailed assessment of Sindbis (SIN) replicon vectors expressing HIV-1 envelope protein (Env) for the induction of cell-mediated and humoral immune responses in a small animal model. SIN-derived virus-like particles (VLP) elicited Env-specific antibody responses that were detectable after boosting with recombinant Env protein. This priming effect could be mediated by replicon activity alone but may be enhanced by Env attached to the surface of VLP, offering a potential advantage for this mode of replicon delivery for Env based vaccination strategies. In contrast, the Env-specific CTL responses that were elicited by SIN-VLP were entirely dependent on replicon activity. SIN-VLP priming induced more durable humoral responses than immunization with protein only. This is important from a vaccine perspective, given the intrinsic tendency of Env to induce short-lived antibody responses in the context of vaccination or infection. These results indicate that further efforts to enhance the magnitude and durability of the HIV-1 Env-specific immune responses generated by Sindbis vectors, either alone or as part of prime-boost regimens, are justified.
Assuntos
Vacinas contra a AIDS/genética , Replicon , Sindbis virus/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Vacinas contra a AIDS/imunologia , Animais , Linhagem Celular , Feminino , Genes env , Vetores Genéticos , Anticorpos Anti-HIV/sangue , HIV-1/imunologia , Imunidade Celular , Imunidade Humoral , Camundongos , Camundongos Endogâmicos BALB C , RNA Viral/imunologia , Sindbis virus/genética , Transfecção , Vacinação/métodos , Vacinas de Partículas Semelhantes a Vírus/genética , Vacinas de Partículas Semelhantes a Vírus/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologiaRESUMO
We report here on the use of a Sindbis virus-based DNA-launch RNA replicon vector (pSIN-HA) that expresses influenza hemagglutinin (HA) as an immunogen. Immunization of mice with pSIN-HA generated anti-HA antibody and CTL responses and resulted in lower lung viral titers after influenza challenge when compared to controls. Importantly, immunization with a low dose of pSIN-HA mediated significantly reduced lung viral titers following challenge at 43 weeks after the final immunization. In contrast, immunization with a non-replicon DNA vector expressing HA failed to mediate reduced lung viral titer at the same dose. This demonstrated the dose-sparing capacity of the SIN vector system and its ability to stimulate long-term memory responses, properties that are highly desirable in any vaccine formulation.