Sulfatide administration leads to inhibition of HIV-1 replication and enhanced hematopoeisis.

Abstract

The pathogenesis of HIV-1 infection is a complex process in which Natural Killer (NK) and Natural Killer T (NKT) cells play an important role. NKT cells express markers for NK cells and a TCR of the conventional T cells and recognize lipid antigens presented by the non-polymorphic CD1 molecule. CD1d-restricted type I NKT cells express an invariant TCR and can recognize αGalCer, whereas a major subset of type II NKT expressing diverse TCR can recognize a self-glycolipid, sulfatide. It has been shown that CD4+ type I NKT cells are infected by HIV-1 and decreased in HIV-1-infected individuals. However, their exact role in HIV-1 infection as well as the biology and function of the type II NKT cell subset in HIV-1 infection and disease progression are not known. Our earlier studies have shown that activation of CD1d-restricted type II NKT cells by sulfatide and their interactions with plasmacytoid dendritic (pDC) and myeloid dendritic (mDC) cells result in anergy induction in type I NKT cells in several models. Here we used SCID-Hu (Thy/Liv) animals, co-implanted with human fetal liver and thymus, and found that these implants contain both type I and type II NKT cells, CD161+CD3+ NKT cells, NK cells and dendritic cells during HIV-infection. We found that the administration of sulfatide (bi-weekly, 20 μg/animal, i.p.) in SCID-Hu animals inhibits HIV-1 replication more efficiently than treatment with the nucleoside analog reverse transcriptase inhibitor, AZT. Virus replication was lowered significantly up to 4-8 weeks post infection. Furthermore sulfatide administration also resulted in significant retention of hematopoeisis that is lost during HIV-1 infection. Advantageously, sulfatide administration itself was not associated with anemia or bone marrow suppression, that are severe side effects of HAART. Since the CD1d-mediated immune pathway is highly conserved between rodents and humans, sulfatide treatment may represent a novel HLA-independent approach for intervention of HIV-1 pathogenesis.