Identification of a factor produced by anti-HIV CD4+ T cells induced by dendritic cell-based immunization in the hu-PBL-SCID mice

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We have previously reported that immunization of the severe combined immunodifficiency (SCID) mice reconstituted with human peripheral blood mononuclear cells (PBMC) (hu-PBL-SCID mice) with inactivated human immunodeficiency virus type-1-pulsed (HIV-1)-autologous dendritic cells (HIV-DC) elicits HIV-1-reactive CD4^+ T cells that produce an as yet to be defined novel soluble factor in vitro with anti-viral properties against CCR5 tropic-(R5) HIV-1 infection. These findings led us to perform studies designed to identify the lineage of the cell that synthesizes such a factor in vivo and define the epitopes of HIV-1 protein that have specificity for the induction of such anti-viral factor. Results of our studies show that this property is a function of CD4^+ but not CD8^+ T cells. Human CD4^+ T cells were thus recovered from the HIV-DC-immunized hu-PBL-SCID mice and were re-stimulated in vitro by co-culture for 2 days with autologous adherent PBMC as antigen presenting cells (APC) previously pulsed with inactivated HIV-1 in IL-2-containing medium to expand HIV-1-reactive CD4^+ T cells. Aliquots of these re-stimulated CD4^+ T cells were then co-cultured with similar APC's that were previously pulsed with 10 mg/ml of a panel of HIV-1 peptides for an additional 2 days, and their culture supernatants were examined for the production of both the R5 HIV-1 suppression factor and IFN-g. The data presented herein show that the HIV-1 primed CD4^+ T cells produced the R5 suppression factor in response to a wide variety of HIV-1 gag, env, pol, nef or vif peptides, depending on the donor of the CD4^+ T cells. Simultaneous production of human interferon (IFN)-g was observed in some cases. These results indicate that human CD4^+ T cells in PBMC of HIV-1 naive donors have a wide variety of HIV-1 epitope-specific CD4^+ T cell precursors that are capable of producing the R5 HIV-1 suppression factor upon DC-based vaccination with whole inactivated HIV-1.