A multi-institutional group that includes investigators in Africa and Europe seeks to develop combination immunoprophylaxis against intrapartum transmission of HIV-1 clade C, a subtype that is responsible for ca. 50 percent of all HIV-1 infections worldwide. Our approach is based on 1) the paradigm of the successful active + passive immunization against maternal transmission of the hepatitis B virus, an enveloped virus distantly related to HIV-1 and transmitted in similar fashion; 2) our ability to obtain sterilizing immunity in neonatal macaques given prophylaxis with a triple combination of highly neutralizing human monoclonal antibodies (mAbs) after mucosal challenge with SHIV-vpu+, a chimeric virus encoding env of HIVIIIB; and 3) the partial protection we achieved in infant rhesus macaques vaccinated with DNA expression vectors boosted with gp160, and challenged i.v. with SHIV-vpu+. Based on these encouraging data, we propose 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 from 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 neonatal macaques against oral SHIVenvC challenge. Our group also includes collaborating investigators who are recognized for their expertise in the epidemiology of HIV infection in developing countries, phylogeny of primate lentiviruses, antiviral humoral immune responses, and vaccine 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 are also 2 superb primate research facilities, whose staff have expertise in primate neonatology and lentivirology. Through these collaborations, the group will have access to retrovirus-free rhesus macaque breeding colonies. 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, many of whom already work effectively as a team, will ensure that this program will reach its goal.
