This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. An effective preventive vaccine for human immunodeficiency virus type 1 (HIV-1) infection remains elusive after 20 years of intense research activities. One significant challenge is the highly restricted nature of HIV-1 for human immune cells, which has precluded vaccine testing in small animal model systems. Such animal models would recapitulate adaptive immune responses as they occur following vaccination in humans. The best means to test candidate vaccine efficacy is through its administration to the primary host, followed by challenges with a spectrum of viral strains present in a population of interest. Recent work from others and our laboratory demonstrated that human effectors of adaptive immunity can be transferred and are functional in rodents. Such a rodent model system contains human antigen presenting dendritic cells (DC), T and B cells, and permits infection by HIV-1. Human peripheral blood lymphocytes transplanted into nonobese diabetic severe combined immunodeficient mice (PBL, hu-PBL-NOD/SCID) can elicit human HIV-1 specific cytotoxic T lymphocytes, neutralizing antibody responses and provide protection against viral challenge. We will investigate HSV-1 amplicon vectors encoding subtype C HIV-1 envelope and Gag, Pol, Nef proteins for immunogenicity by assessing their interaction with DC in vitro, and the ability of transduced DC to stimulate humoral and cellular immune responses in vivo. We will examine selected vaccine candidates for the ability to control viral replication and preserve CD4+T lymphocytes after in vivo challenge of DC-vaccinated hu-PBL-NOD/SCID mice with several primary viral isolates from subtypes C and B. Such work will uncover efficacy of subtype C vaccine, explore correlates of protection and speed the process of rational immunogen selection leading to human vaccine testing.
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