HIV-1 Nef-mediated inhibition of T cell migration and its molecular determinants.
Lymphocyte trafficking is a multistep, intricate process and involves a number of host factors such as integrins and chemokine receptors on lymphocytes, adhesion molecules on endothelial cells, and chemokines present in the local microenvironment. Previous studies have shown that HIV-1 Nef inhibits T cell chemotaxis in response to the physiological ligand SDF-1alpha [( 1) ]. In this study, we aimed to gain a better understanding of the inhibitory mechanisms and to define the molecular determinants of HIV-1 Nef for this phenotype. We showed that HIV-1 Nef inhibited transwell and transendothelial migration of T cells. Specifically, HIV-1 Nef protein impaired T cell chemotaxis toward SDF-1alpha without altering CXCR4 expression. Moreover, we showed that HIV-1 Nef protein down-modulated LFA-1 expression on T lymphocytes and diminished adhesion and polarization of T lymphocytes and as a result, led to decreased migration across the endothelium. Furthermore, we showed that the myristoylation site and DeltaSD domain played important roles in Nef-mediated inhibition of transwell and transendothelial migration and polarization of T lymphocytes; however, different sites or domains were needed for Nef-mediated LFA-1 down-modulation and impaired adhesion of T lymphocyte. Taken together, these results demonstrated that HIV-1 Nef inhibited T lymphocyte migration at multiple steps and suggest that membrane localization and intracellular signaling events likely contribute to the inhibitory effects of Nef on T cell migration and subsequently, the pathobiology of the HIV-1 Nef protein.
Park
In-Woo
IW
Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, R2 302, 950 W. Walnut St., Indianapolis, IN 46202, USA. parki@iupui.edu
He
Johnny J
JJ
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000276:immunology / Q000821:virology; D005434:Flow Cytometry; D005784:Gene Amplification; D017930:Genes, Reporter; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D019169:Jurkat Cells / Q000821:virology; D009154:Mutation; D015183:Restriction Mapping; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology / Q000821:virology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D017931:DNA Primers; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1