THE ANTI-ALPHA-4/BETA-7 MONOCLONAL ANTIBODY PROJECT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. One of the earliest organs affected by HIV and SIV infection is the GI tract. Moreover, the bulk of viral replication occurs in this compartment leading to rapid and permanent elimination of CD4+ T cells, in particular those co expressing the viral co-receptor CCR5. What is not clear to date is whether the continuous viral replication requires a constant influx of new CD4 targets or not, which would open a novel therapeutic vista by blocking traffic of potential target cells to the gut. Among the molecules dictating traffic to the gut the heterodimeric integrin ¿4¿7 has gained particular attention especially in the therapy of gut inflammatory syndromes such as IBD, UC and Crohn's Disease. We have pre-treated 4 rhesus macaques with a primatized monoclonal antibody specific to ¿4¿7prior to infection with SIVmac239 SIV replication and immune responses to the virus were compared in these monkeys and control animals given SIV only. Blocking cell traffic to the gut resulted in profound differences in the dynamic of the acute SIV infection lowering and delaying the peak of acute SIV replication and causing a shift of the main replication site from the gut to central lymphatic organs. Results of this pilot study have been accepted in the Journal of Immunology. Future analyses will investigate prolonged blockade of cell traffic to the gut during chronic infection and after mucosal challenge.