A multi-institutional, multi-national group seeks funding to develop combination immunoprophylaxis against intrapartum transmission of HIV clade C, a subtype responsible for approximately of all HIV infections worldwide. Our approach is based upon: 1) the paradigm + passive immunization against maternal. Our approach is based upon: 1) the paradigm of the successful active + passive immunization against maternal transmission of hepatitis B virus, an enveloped virus distantly related to HIV-1; 2) the solid protection we achieved in all (mAbs) and challenged orally with SHIV-vpu+ (a chimeric virus encoding HIVIIIB env); 3) the partial protection we achieved in neonatal macaques with human mAbs against challenges with pathogenic SHIV89.6P (encoding env of the primary dual-tropic HIV89.6); and 4) the partial protection we achieved in infant macaques vaccinated with DNA expression vectors, boosted with gp160, and challenged i.v. with SHIV-vpu+ initially and with SHIV89.6P sequentially. Encouraged by these data, we propose to extend the active + passive immunization approach against HIV clade C. We plan to evaluate this approach to extend the active + passive immunization approach against HIV clade C. We plan to evaluate this approach in a macaque model with a chimeric simian/human immunodeficiency virus encoding the env gene of a primary clade C strain that had been transmitted form an African mother to her infant. This new chimeric virus will be designated SHIVenvC. In Project 1, we will test the hypothesis that novel mAbs can be found with broad reactivity against HIV clade C by using an in vitro system involving intact virions. Project 2 will address passive immunoprophylaxis with combinations of neutralizing mAbs in cultured cells and in neonatal macaques that will be challenged orally with SHIVenvC. In Project 3, DNA prime-protein boost strategies will be explored in infant macaques. Finally, we will test whether active + passive vaccination can protect infant macaques against oral SHIVenvC challenge at birth and several months later, to assess whether protection is long-lasting. Of group includes collaborators recognized for their expertise in the phylogeny of primate lentiviruses, anti-viral humoral immune responses, and vaccines development. It represents a truly international effort, as investigators from various regions of the United States, Austria and Africa will work on the common goal. Included is also a superb primate research facility, whose staff have expertise in primate neonatology and lentivirology. Together, the investigators and the various institutions offer expertise that is not available at any individual laboratory or institution. The productivity of the collaborating investigators, may of whom already work effectively as a team, will ensure that this program will reach its goal.
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