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HIV-1 Nef Promotes Endocytosis of Cell Surface MHC Class II Molecules via a Constitutive Pathway¹

Ashutosh Chaudhry^2,*, Divya Anna Verghese^2,*, Suman Ranjan Das, Shahid Jameel, Anna George^*, Vineeta Bal^*, Satyajit Mayor and Satyajit Rath^3,*

^* National Institute of Immunology, New Delhi, India; International Centre for Genetic Engineering and Biotechnology, New Delhi, India; and National Centre for Biological Sciences, Bangalore, India

HIV-1 Nef has been reported to disrupt MHC class II (MHCII)-mediated Ag presentation by a dual strategy that comprises a reduction in cell surface levels of peptide-loaded mature MHCII molecules and a up-regulation of immature MHCII molecules. We show that Nef achieves relocation of MHCII away from the cell surface in monocytic cells by both delaying its transport to the cell surface and by accelerating endocytic removal of cell surface MHCII to a lysosomal compartment. Nef-induced MHCII endocytosis is cholesterol-sensitive but clathrin- and dynamin-independent. Internalized MHCII molecules traverse the early endosomal system and colocalize with pinocytic cargo before reaching lysosomes. Nef-triggered MHCII endocytosis requires Rab5 activity and lyst function, whereas lysosomal trafficking of internalized MHCII molecules requires Rab7 activity. We further show that a similar pathway can remove peptide-MHCII complexes from the surface of monocytic cells not expressing Nef. Our data suggest that Nef uses mechanisms involved in normal MHCII recycling and turnover to mediate the delivery of cell surface MHCII to a lysosomal destination. Thus, Nef-mediated endocytosis of MHCII provides a novel perspective on the regulation of normal MHCII trafficking.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Departments of Science and Technology, and Biotechnology, Government of India (to A.G., S.R., and V.B.). S.R.D. was supported by a fellowship from the Council for Scientific and Industrial Research, Government of India. National Institute of Immunology and International Centre for Genetic Engineering and Biotechnology are supported by the Department of Biotechnology, Government of India.

² A.C. and D.A.V. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Satyajit Rath, National Institute of Immunology, Aruna Asaf Ali Road, New Delhi 110067, India. E-mail address: satyajit{at}nii.res.in

⁴ Abbreviations used in this paper: MHCII, MHC class II; Bg, beige; BMDM, bone marrow-derived monocyte; CA, constitutively active; DN, dominant negative; Dyn, dynamin; eGFP, enhanced GFP; Ii, invariant chain; MBCD, methyl-β-cyclodextrin; MHCI, MHC class I; NA, numerical aperture; PIK, phosphatidylinositol kinase; pMHCII, peptide-MHCII complex; sh-Dyn, short interfering RNA for Dyn-2; Tf, transferrin; Wm, wortmannin; WT, wild type.