16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

THE NEF-TCR INTERACTION: POTENTIAL ROLE IN AUGMENTATION OF T-CELL SIGNALING

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0205

Kim W.M., Sigalov A.B., Stern L.J.
University of Massachusetts Medical School, Department of Pathology, Worcester, Massachusetts, United States

BACKGROUND: Expressed in abundance during the early stages of viral replication, HIV/SIV negative factor (Nef) plays an important role in determining the pathogenesis of an HIV/SIV infection and its progression to AIDS. Notable among Nef's essential functions is augmentation of T cell activation, presumably through its interaction with the ζ-chain of the T cell receptor (TCRζ), the major signaling component of TCR. Although different Nef variants have been reported to specifically bind the TCRζ, the role of this interaction and the global manner by which Nef modulates T cell activation remains unknown. We postulate that the combination of Nef's specific interaction with TCRζ and the oligomeric nature of both proteins leads to the formation of Nef-TCRζ heterooligomeric clusters that prime the T cell for hyperactivation.

METHODS: In order to characterize the interaction of different variants of HIV/SIV Nef with TCRζ, gel filtration (GF) and surface plasmon resonance experiments were performed with soluble recombinant forms of Nef and TCRζ. The oligomeric states of Nef and TCRζcyt were studied by GF and dynamic light scattering.

RESULTS: The conserved core domain of several Nef variants forms stable heterodimers with the cytoplasmic domain of TCRζ (TCRζcyt) with fundamental 1:1 binding stoichiometry. The TCRζcyt homodimer was disrupted in the presence of Nef to form a stable 1:1 Nef-TCRζ heterocomplex.

CONCLUSIONS: By binding specifically to the cytoplasmic domain of TCRζ, Nef may function as a biological crosslinker capable of clustering multiple TCR complexes from within the intracellular compartment. The potential for Nef to augment T cell activation through the formation of TCR clusters presents a novel mechanism of Nef function and T cell signaling.

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2006-08-13
ThAa0205

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