Abstract
We have previously reported that immunization of the severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood mononuclear cells (PBMC) (hu-PBL-SCID mice) with inactivated human immunodeficiency virus type-1 (HIV-1)-pulsed-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 vitro 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 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 μg/ml of a panel of HIV 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-Υ. 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)-Υ 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.
Highlights
Virus specific CD4þ helper T (Th) cell responses have been shown to play an essential role in the maintenance of effective immune responses in a variety of animal models [3,12,20,32,34]
These data indicate that CD8þ T cells are not required for the production of the R5 Human immunodeficiency virus type 1 (HIV-1) suppression factor in vivo, and that the HIV-immune human CD4þT cell population is the major source for the R5 HIV-1 suppression factor in vivo
Our laboratory has previously documented the synthesis of a soluble factor by CD4þ T cells isolated from severe combined immunodeficiency (SCID) mice previously engrafted with a mixture of human peripheral blood mononuclear cells (PBMC)’s and HIV-1-pulsed autologous dendric cells (DC)’s which suppressed infection of R5 HIV-1 in vitro [39]
Summary
Virus specific CD4þ helper T (Th) cell responses have been shown to play an essential role in the maintenance of effective immune responses in a variety of animal models [3,12,20,32,34]. In addition to the traditional function of CD4þ T cells in facilitating the generation of HIV-1 specific CD8þ T cells and the synthesis of antibodies, CD4þ Th cells from HIV-1 infected patients have been shown to exert anti-viral effects by direct lysis of HIV-1 infected target cells by HIV-1 gag specific CD4þ T cells [18] and by the secretion of a variety of HIV-1 suppression factors [1,15,31,41] These findings together suggest that CD4þ T cells from HIV-1 infected and/or immunized individuals have acquired a series of unique anti-viral activity which may contribute to the control of viremia and the detailed studies of the mechanisms by which such activity is acquired and induced appears warranted. Of interest was the finding that the factor was not effective in controlling R5 HIV-1 infection of CCR5expressing CD4þT cell lines
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