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. Lack of information on mechanisms of protection against HIV/SIV infection remains one of the leading obstacles to the development of a safe and effective AIDS vaccine. Vaccination of macaques with attenuated SIV strains has consistently proved to be the most effective means of inducing protection against pathogenic SIV challenge and offers the best available experimental model to define specific mechanisms responsible for protection. Previous studies from our group have provided evidence that SIV-specific CD8-positive T cell and humoral responses both contribute to protective immunity induced by SIVdeltanef but have not been able to assess their relative importance or the potential contributions of novel adaptive or innate immune responses to protection. The goal of this study is to utilize a number of novel techniques to carry out a comprehensive analysis of the role of adaptive and innate immune responses in mediating protection induced by SIV?nef against vaginal challenge, one of the most important modes of HIV transmission. SIV?nef infection resulted in significant increases in natural killer cells, SIV-specific CD8-positive T cell responses and antibody responses in the first 2-5 weeks after infection;these responses were associated with minimal protection against vaginal SIVmac251 challenge at 5 weeks after vaccination. Both humoral and cellular immune responses display progressive evidence of maturation from 5 to 20 weeks after vaccination, associated with substantial, though still incomplete, protection against vaginal SIVmac251 challenge. These studies results are yielding a comprehensive delineation of the signature characteristics of protective immunity against lentiviral infection.
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