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. To evaluate the activity of antibody CD4-IgG2 against SIVmac239 in macaques in protection against mucosal challenge and in an ongoing infection. To evaluate the effects of having specific T cells and neutralizing antibody (CD4-IgG2) present together in macaques before challenge with SIVmac239. The neutralizing antibody levels are chosen to be below those giving sterile protection as determined in Aim 1 and correspond more to those that could be achieved through vaccination. To investigate the potential of antibody and T cell responses to act in concert, we first studied the dose at which the antibody, here CD4-IgG2, can confer partial protection against mucosal SIVmac239 challenge in rhesus macaques. Results from this experiment appeared to differ from results previously described in a SHIV162P4 intravaginal challenge-b12 neutralizing monoclonal antibody model system: A lower than predicted CD4-IgG2 level was able to confer sterilizing protection in three out of four total treated and challenged animals. The animal that became infected in spite of receiving CD4-IgG2 recombinant antibody showed no apparent difference as compared to the control animals regarding the kinetics of the plasma viral burden. To understand whether the absence of impact of CD4-IgG2 administration in the unprotected animal was eventually due to the rapid emergence of an escape mutant, as described in the hu-PBL-SCID mouse model of HIV-1 infection, we performed a bulk sequencing of the PCR product of the plasma virus population trough the envelope region. By day seven post-infection the CD4-IgG treated infected animal harbored mutant SIVmac239 virus with one non-synonymous mutation in the C4 region of the envelope. This mutation was the only reproducible change in the envelope. Cloning is underway to corroborate this finding. This research used WNPRC Animal Services and Immunogenetics & Virology Services.
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