The Journal of Immunology, Vol 149, Issue 1 285-294, Copyright © 1992 by American Association of Immunologists

ARTICLES

Internalization of HIV glycoprotein gp120 is associated with down- modulation of membrane CD4 and p56lck together with impairment of T cell activation

D Cefai, M Ferrer, N Serpente, T Idziorek, A Dautry-Varsat, P Debre and G Bismuth
Laboratoire d'Immunologie Cellulaire et Tissulaire, CNRS URA 625, CERVI, Paris, France.

We previously demonstrated that long term treatment of the Ag-specific CD4+ T cell clone P28D with soluble HIV envelope glycoprotein gp120 results in a marked impairment of CD3/TCR-mediated responses. In this report, to further understand these inhibitory effects, the binding properties and internalization of gp120 have been investigated, in parallel with functional studies, in long term incubations of P28D cells with gp120. Immunofluorescence studies show that surface-bound gp120 level is maximal within 1 h of incubation at 37 degrees C and then gradually decreases. This decrease is accompanied by a progressive down-modulation of membrane CD4 (30-35% loss over a 18-h incubation period) without concomitant alteration of the CD4 mRNA steady-state level. Similar experiments performed with 125I-labeled gp120 demonstrate that the glycoprotein is progressively internalized (up to 35% internalized material after 18 h) and that it accumulates inside the cells. Confocal microscopy studies show that internalized gp120 is concentrated in localized intracellular compartments. CD4 also accumulates in compartments with a similar localization and is stained with mAb OKT4 but not with mAb OKT4a. Concomitantly to internalization of gp120 and disappearance of membrane CD4, a correlated loss of the CD4-associated tyrosine kinase p56lck is evidenced. Interestingly, a progressive impairment of the P28D responses to specific Ag or to anti- CD3 mAb is also observed. Inhibitions of T cell proliferation increase with the degree of both CD4 and p56lck down-modulation. Removal of exogenous gp120 results in a rapid and spontaneous release of internalized gp120 into a degraded form. A progressive restoration of CD4 and p56lck levels is also noticed. In parallel, CD3/TCR-mediated responses of clone P28D are fully recovered. Altogether, our results suggest that HIV-1 glycoprotein gp120 is able to down-modulate membrane CD4 presumably by a cointernalization process and to further down- modulate the associated p56lck. This dual phenomenon is presumably involved in the direct immunosuppressive effect of gp120 on the CD3/TCR- mediated activation pathway.

This article has been cited by other articles:

				D. S. Green, D. M. Center, and W. W. Cruikshank Human Immunodeficiency Virus Type 1 gp120 Reprogramming of CD4+ T-Cell Migration Provides a Mechanism for Lymphadenopathy J. Virol., June 1, 2009; 83(11): 5765 - 5772. [Abstract] [Full Text] [PDF]

				G. Koopman, D. Mortier, S. Hofman, M. Koutsoukos, W. M. J. M. Bogers, B. Wahren, G. Voss, and J. L. Heeney Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian-human immunodeficiency virus strain 89.6p-infected macaques J. Gen. Virol., April 1, 2009; 90(4): 915 - 926. [Abstract] [Full Text] [PDF]

				A. M. Nyakeriga, C. J. Fichtenbaum, J. Goebel, S. A. Nicolaou, L. Conforti, and C. A. Chougnet Engagement of the CD4 Receptor Affects the Redistribution of Lck to the Immunological Synapse in Primary T Cells: Implications for T-Cell Activation during Human Immunodeficiency Virus Type 1 Infection J. Virol., February 1, 2009; 83(3): 1193 - 1200. [Abstract] [Full Text] [PDF]

				A. K. L. Cheung, A. Abendroth, A. L. Cunningham, and B. Slobedman Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells Blood, December 1, 2006; 108(12): 3691 - 3699. [Abstract] [Full Text] [PDF]

				C. Barat, P. Gervais, and M. J. Tremblay Engagement of ICAM-3 Provides a Costimulatory Signal for Human Immunodeficiency Virus Type 1 Replication in both Activated and Quiescent CD4+ T Lymphocytes: Implications for Virus Pathogenesis J. Virol., June 15, 2004; 78(12): 6692 - 6697. [Abstract] [Full Text] [PDF]

				C. L. Bristow, D. R. Mercatante, and R. Kole HIV-1 preferentially binds receptors copatched with cell-surface elastase Blood, December 15, 2003; 102(13): 4479 - 4486. [Abstract] [Full Text] [PDF]

				A. M. Masci, M. Galgani, S. Cassano, S. De Simone, A. Gallo, V. De Rosa, S. Zappacosta, and L. Racioppi HIV-1 gp120 induces anergy in naive T lymphocytes through CD4-independent protein kinase-A-mediated signaling J. Leukoc. Biol., December 1, 2003; 74(6): 1117 - 1124. [Abstract] [Full Text]

				A. Bachis, E. O. Major, and I. Mocchetti Brain-Derived Neurotrophic Factor Inhibits Human Immunodeficiency Virus-1/gp120-Mediated Cerebellar Granule Cell Death by Preventing gp120 Internalization J. Neurosci., July 2, 2003; 23(13): 5715 - 5722. [Abstract] [Full Text] [PDF]

				A. Papkalla, J. Munch, C. Otto, and F. Kirchhoff Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity and Replication Independently of Viral Coreceptor Tropism J. Virol., July 17, 2002; 76(16): 8455 - 8459. [Abstract] [Full Text] [PDF]

				P. Bostik, P. Wu, G. L. Dodd, F. Villinger, A. E. Mayne, V. Bostik, B. D. Grimm, D. Robinson, H.-J. Kung, and A. A. Ansari Identification of Protein Kinases Dysregulated in CD4+ T Cells in Pathogenic versus Apathogenic Simian Immunodeficiency Virus Infection J. Virol., December 1, 2001; 75(23): 11298 - 11306. [Abstract] [Full Text]

				A. Abendroth, G. Morrow, A. L. Cunningham, and B. Slobedman Varicella-Zoster Virus Infection of Human Dendritic Cells and Transmission to T Cells: Implications for Virus Dissemination in the Host J. Virol., July 1, 2001; 75(13): 6183 - 6192. [Abstract] [Full Text] [PDF]

				N. Madani and D. Kabat Cellular and Viral Specificities of Human Immunodeficiency Virus Type 1 Vif Protein J. Virol., July 1, 2000; 74(13): 5982 - 5987. [Abstract] [Full Text]

				I. Segura, C. Delmelle-Wibaut, M. Janssens, Y. Cleuter, A. van den Broeke, R. Kettmann, and K. E. Willard-Gallo Human Immunodeficiency Virus Type 2 Produces a Defect in CD3-gamma Gene Transcripts Similar to That Observed for Human Immunodeficiency Virus Type 1 J. Virol., June 1, 1999; 73(6): 5207 - 5213. [Abstract] [Full Text]

				D. Misse, M. Cerutti, N. Noraz, P. Jourdan, J. Favero, G. Devauchelle, H. Yssel, N. Taylor, and F. Veas A CD4-Independent Interaction of Human Immunodeficiency Virus-1 gp120 With CXCR4 Induces Their Cointernalization, Cell Signaling, and T-Cell Chemotaxis Blood, April 15, 1999; 93(8): 2454 - 2462. [Abstract] [Full Text] [PDF]

				S. Gratton, M. Julius, and R.-P. Sekaly lck-Independent Inhibition of T Cell Antigen Response by the HIV gp120 J. Immunol., October 1, 1998; 161(7): 3551 - 3556. [Abstract] [Full Text] [PDF]

				D. Cefai, H. Schneider, O. Matangkasombut, H. Kang, J. Brody, and C. E. Rudd CD28 Receptor Endocytosis Is Targeted by Mutations That Disrupt Phosphatidylinositol 3-Kinase Binding and Costimulation J. Immunol., March 1, 1998; 160(5): 2223 - 2230. [Abstract] [Full Text] [PDF]

				J. Zhang, K. Salojin, and T. L. Delovitch Sequestration of CD4-Associated Lck from the TCR Complex May Elicit T Cell Hyporesponsiveness in Nonobese Diabetic Mice J. Immunol., February 1, 1998; 160(3): 1148 - 1157. [Abstract] [Full Text] [PDF]