This proposal will provide the candidate with the intensive training necessary to study the cellular immune response to neonatal immunodeficiency virus infection. The applicant will be sponsored at the Dana-Farber Cancer Institute and Harvard Medical School by Dr. Ruth M. Ruprecht, an expert in pathogenesis and prophylaxis of retrovirus infection. The research will lead to a better understanding of neonatal simian immunodeficiency virus (SIV) pathogenesis. Maternal HIV-1 transmission occurs in utero, intrapartum, and by breastfeeding. The sponsor developed a primate model for congenital infection following intra-amniotic exposure of macaques to SIV in utero; the applicant developed a model for peripartum infection following oral exposure of neonatal macaques to cell-free SIV at delivery, thereby providing a way to study the neonatal immune response to mucosal immunodeficiency virus exposure.
The specific aims of this proposal are to: 1. Compare cellular immunity developing after in utero versus peripartum infection with pathogenic SIV. Do in utero exposed neonatal macaques have impaired immune responses to SIV? Are responses different in neonates exposed orally to SIV at birth? Studies of human neonates infected with HIV-1 indicate impaired cellular immunity in vitro. Is a similar defect present in macaques? 2. Evaluate the cellular immune response that develops following neonatal versus adult infection with """"""""attenuated"""""""", nef-deleted SIV. This virus is nonpathogenic in adult rhesus monkeys and protect them against subsequent challenge with pathogenic SIV. In contrast, the applicant has demonstrated that this """"""""attenuated"""""""" virus is pathogenic in orally exposed neonatal monkeys. What mechanism affords protection to adult monkeys? Is it impaired in neonates? This proposal will train the applicant to investigate the neonatal cellular immunity to virus infection. Evaluation of the neonatal cellular immune response following mucosal infection is highly significant, providing a foundation for the development of strategies to prevent neonatal infection.
| Rasmussen, Robert A; Hofmann-Lehman, R; Montefiori, D C et al. (2002) DNA prime/protein boost vaccine strategy in neonatal macaques against simian human immunodeficiency virus. J Med Primatol 31:40-60 |
| Hofmann-Lehmann, R; Vlasak, J; Rasmussen, R A et al. (2001) Postnatal passive immunization of neonatal macaques with a triple combination of human monoclonal antibodies against oral simian-human immunodeficiency virus challenge. J Virol 75:7470-80 |
