Zeitschrift für klinische und zelluläre Immunologie
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Hematopoietic Stem Cell-Based Therapy for HIV Disease: A Role for Regulatory T Cells

Josef Bodor, Petr Kobylka and Gero Huetter

The goal of this review is to develop insight and understanding of the effect of deleting the chemokine receptor CCR5 in T cells, and its interplay with immune regulation of Human Immunodeficiency Virus type–1 (HIV-1), to enable a novel technology platform to cure HIV disease. A critical point is the use Hematopoietic Stem Cell (HSC) transplantation of the cells resistant to HIV such as CCR5Δ32 cells, which harbor deletion in the CCR5 promoter. Such mutations, which spontaneously occur in 4-15% of the European or US populations confer resistance to CCR5-tropic HIV-1 in homozygous individuals and could cure HIV-1 disease based on the outcome of bone marrow engraftment in HIV⁺ leukemic patients using a CCR5Δ32 homozygous donor (e.g. ‘Berlin Patient’). However, potential shift of HIV tropism to CXCR-4 tropic strains of HIV-1 is limiting after HSC transplantation with CCR5Δ32/Δ32 donor since it could lead to recurrence of viremia (e.g. ‘Essen patient’). In addition, patients receiving allogeneic bone marrow transplantation often suffer from Graft-Versus-Host Disease (GvHD), and for that reason HIV infection is not considered an indication, unless a hematologic malignancy warrants transplantation. To advance this field, it is, however, vital i) to search for novel determinants to HIV susceptibility using genome-wide analyses and ii) exploit mechanisms, which play a crucial role in amelioration of GvHD such as repression of conventional CD4⁺ T cells (Tcons) by naturally occurring regulatory CD4⁺CD25⁺ T cells (nT_regs). Transfer of cyclic AMP (cAMP) from nT_regs to Tcons underpins function of potent transcriptional repressor termed inducible cAMP early repressor (ICER) leading to suppression of interleukin-2 (IL-2) synthesis in Tcons. Further understanding of the mechanisms of immunological self-tolerance will also provide insights into how strong immune responses such as graft rejection could be restrained and engraftment of HIV resistant cells in HIV⁺ leukemic patients could be augmented.