Abstract
Nef, an accessory protein of the Human Immunodeficiency Virus type 1 (HIV-1), is dispensable for viral replication in cell culture, but promotes virus replication and pathogenesis in the infected host. Acting as protein-interaction adaptor, HIV-1 Nef modulates numerous target cell activities including cell surface receptor expression, cytoskeletal remodeling, vesicular transport, and signal transduction. In infected T-lymphocytes, altering T-cell antigen receptor (TCR) signaling has long been recognized as one key function of the viral protein. However, reported effects of Nef range from inhibition to activation of this cascade. Recent advances in the field begin to explain these seemingly contradictory observations and suggest that Nef alters intracellular trafficking of TCR proximal machinery to disrupt plasma membrane bound TCR signaling while at the same time, the viral protein induces localized signal transduction at the trans-Golgi network. This review summarizes these new findings on how HIV-1 Nef reprograms TCR signalling output from a broad response to selective activation of the RAS-Erk pathway. We also discuss the implications of these alterations in the context of HIV-1 infection and in light of current concepts of TCR signal transduction.
Highlights
T-cell receptor signaling Development, proliferation and immune functions of Tlymphocytes are regulated by their activation state [1]
Signals emanating from Lymphocyte-specific protein tyrosine kinase (Lck) trigger T-Cell Antigen Receptor (TCR) proximal signal transduction and are diversified and channeled to multiple downstream signaling pathways by Linker of Activated T-cells (LAT)-SLP-76 adaptor scaffolds that act as mirco-signalosomes (Figure 1) [17,18]
Since molecular and functional differences between simian immunodeficiency viruses (SIV) and Human Immunodeficiency virus (HIV)-1 Nef proteins in this context were already discussed extensively, this review focuses on recent developments that enhance our understanding of how Human Immunodeficiency Virus type 1 (HIV-1) Nef modulates TCR signaling in infected CD4+ T-lymphocytes
Summary
T-cell receptor signaling Development, proliferation and immune functions of Tlymphocytes are regulated by their activation state [1]. This effect may synergize to potentiate transcriptional activation of downstream target genes with the ability of Nef to (i) promote, via interactions with the IP3 receptor, the release of calcium from intracellular stores [81] and (ii) trigger Erk activity via association with the Nefassociated kinase complex NAKC [101,102,103] Together, these findings provide an explanation for the observed Nef-mediated disruption of early TCR signaling and selective, stimulus-independent sensitization of Figure 2 Model of the effects of HIV-1 Nef on TCR signaling. This disruption does depend on Nef’s ability to target LAT containing vesicles to this yet to be defined intracellular compartment, and requires Nef to interfere with TCR-induced actin dynamics This predicts that in physiological T-cell signaling, dynamic actin remodeling may be critical for translocation of LAT positive vesicles to TCR activation sites, allowing phosphorylation of the adaptor protein and subsequent downstream signaling events.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
