CD4 MEDIATED IMMUNE RECONSTITUTION IN SIV INFECTION

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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. This project is aimed at immune reconstitution of SIV infected macaques comparing autologous CD4+ T cells collected prior to versus post SIV infection and expanded in vitro using anti-CD3/anti-CD28 coated immunobeads. The data suggest that CD4+ T cells collected early post SIV infection either under the umbrella of PMPA chemotherapy or in the absence of, show expansion and immune restorative function similar to pre SIV infection collected cells. However, the data unequivocally show that a marked diminution of viral loads is imperative before initiation of adoptive transfer of autologous CD4 T cells in order to induce potent control of SIV replication. Another main area of investigation was the characterization of the CD4+ T cells as they are being expanded and their behavior beyond the expansion phase at the time of reinfusion to the animal. While the cells uniformly display a central memory phenotype and express all markers of regulatory T cells, these cells conform functionally more to an effector profile based on cytokine secretion and the expression of activation and homing markers. Furthermore, while CCR5 expression is restored following the expansion and these cells become again susceptible to SIV infection, the viral replication appears inefficient compared to the same aliquots of non-expanded CD4 T cells. This property was restricted to R5 tropic viruses and preliminary findings ascribe such "deficiency" to altered CCR5 mediated signaling via the associated Gai/cAMP pathway, while the Gaq pathway controlling chemokine signaling and chemotaxis did not appear affected. Additional investigations into this mechanism are ongoing.