This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.A significant obstacle in the development of an effective preventive vaccine for HIV-1 rests in the absence of a suitable animal model. To this end, humanized mice were generated by reconstitution of newborn Balb/c-Rag2-/-gc-/- mice with human hematopoietic stem cells. Animals were vaccinated with recombinant Adenovirus serotype 5 vectors (rAd5) encoding two derivatives of the HIV-1 clade C envelope proteins (gp145DCFI and gp140DCFI). After a prime-boost rAd5:gp145 immunization, significant cytokine (predominantly IFN-g) and humoral immune responses to both rAd5 and subtype C gp120 were observed. Vaccination with rAd5:gp140 followed by challenge with CCR5-utilizing clade C HIV-1C1157 resulted in the generation of virus-specific antibodies. Notably, vaccination and subsequent HIV-1 challenge induced rapid depletion of na ve CD4+ and effector CD8+ cells from lymphoid tissue of vaccinated humanized mice compared to non-vaccinated controls. The work demonstrates that a human immune system can function in a murine environment. The study also suggests the need for careful monitoring of breakthrough infections in HIV-1 vaccine recipients. We concluded that immunization of humanized mice with adenoviral vector encoding HIV-1 envelope protein induces specific immune responses but not viral protection.
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