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. The World Health Organization estimates that 590,000 children acquire HIV infection each year. While highly active anti-retroviral therapy (HAART) has reduced the morbidity and mortality of HIV infection in the short term, it remains unavailable to much of the world and is not curative. Therefore, an HIV vaccine is urgently needed and breast-feeding infants born to HIV-infected women in the developing world are critical target cohorts for vaccine development. Insights gained from studies of the immunobiology of HIV suggest that an effective HIV vaccine will need to induce strong CD8+ T cell responses, CD4+ T cell responses, and neutralizing antibodies. However, the immune system of young infants is immature as evidenced by increased susceptibility to bacterial and viral infections, inability to respond to some vaccines, and deficiencies in T cell function. Therefore, an HIV vaccine designed for adults will need to be tested and potentially modified to be safe and effective in neonates. The immune system of infant rhesus monkeys resembles that of human infants. Infant monkeys have been utilized to study the use of vaccines that induce protective antibody responses in human infants. The well-developed SIV/rhesus macaque model has provided important insights into the immunobiology of HIV/SIV and a growing repertoire of reagents and methods have become available for detailed immunological analyses. The goal of this research is to develop, in conjunction with the Vaccine and Gene Therapy Institute at the Oregon National Primate Research Center, an immunologically sophisticated model to study T cell and B cell immunity in rhesus macaques and then use this as an animal model for HIV vaccine development for human infants.
The specific aims are: 1) To determine if infant rhesus monkeys are deficient in their capacity to develop antigen-specific T and B cell immunity by comparison of the neonatal monkey to immunologically mature juvenile monkeys with regard to antigen-specific CD8+ and CD4+ T cell responses following vaccination with modified vaccinia virus Ankara (MVA) expressing SIV gag pol (MVA-SIV239 gag pol) and antigen-specific CD4+ T cell responses and antibody titers following vaccination with recombinant SIV Envelope protein (SIVmac239 gp130) in alum adjuvant; and 2) To determine if this MVA/recombinant gp130 vaccination is less protective in infant rhesus monkeys than in juvenile monkeys given a mucosal viral challenge with SIVmac251 by comparison of the degree of viral replication in challenged infants versus juvenile animals and the frequency and tempo of development of simian AIDS in challenged infants versus juvenile animals. To date, the study of the two juvenile groups of animals has been completed. In experimental animals, primed SIV Gag-specific CD8+ T cells were readily detected at frequencies 1/10,000 of total CD8+ T cells at the time of the second immunization (Week 6) in two animals and 3 weeks following the second immunization (Week 9) in all four animals. In control animals, SIV Gag-specific CD8+ T cells were not detected prior to SIV challenge. Following SIV challenge, T cell frequencies increased approximately 10-fold in experimental animals, as high as 1/200 of total CD8+ T cells, and became detectable in control animals (range, 1/10,000 to 1/1000). Interestingly, using soluble tetrameric Mamu-A*01/p11c, CM9 complexes to measure SIV Gag p11c, CM9-specific CD8+ T cells, we first detected responses over baseline in all four animals at Week 9. The study of neonatal animals is nearly completed. Immunogenicity of the vaccine, as measured by tetramer responses, was equivalent in neonates and juveniles. Antibody and additional T cell studies are in progress.
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