Endocytosis of major histocompatibility complex class I molecules is induced by the HIV–1 Nef protein

  title={Endocytosis of major histocompatibility complex class I molecules is induced by the HIV–1 Nef protein},
  author={Olivier Schwartz and Valérie Maréchal and Sylvie Le Gall and François Lemonnier and Jean Michel Heard},
  journal={Nature Medicine},
Like other pathogenic viruses, HIV–1 down–modulates surface expression of major histocompatibility complex class I (MHC–I) molecules in infected cells, thus impairing lysis by cytotoxic T lymphocytes1,2. We have observed that this phenomenon depends on the expression of Nef. nef is an early gene of primate lentiviruses3, which is necessary for maintaining high virus loads and inducing AIDS (ref. 4). Nef is not necessary for viral replication in vitro and stimulates the endocytosis of CD4 (ref… 

HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI 3-kinase-dependent pathway.

It is shown here that endocytosis is not required for Nef-mediated downmodulation of MHC-I molecules, and it is proposed that Nef diverts M HC-1 proteins into a PI 3-kinase-dependent transport pathway that prevents expression on the cell surface.

HIV-1 Nef protein binds to the cellular protein PACS-1 to downregulate class I major histocompatibility complexes

These results support a model in which Nef relocalizes MHC-I by acting as a connector between M HC-I’s cytoplasmic tail and the PACS-1-dependent protein-sorting pathway.

HIV-1 Nef impairs MHC class II antigen presentation and surface expression

It is shown that HIV-1 Nef inhibits MHC II restricted peptide presentation to specific T cells and thus may affect the induction of antiviral immune responses and Cooperation between those mechanisms may enable Nef to efficiently inhibit M HC II function.

Transcription of Preintegrated HIV-1 cDNA Modulates Cell Surface Expression of Major Histocompatibility Complex Class I via Nef

The capacity of HIV-1 to modulate MHC-I is not linked to its ability to integrate, and Nef-mediated evasion of host immune responsiveness might be attributable, in part at least, to transcription from unintegrated viral DNA.

HIV-1 Nef Disrupts Antigen Presentation Early in the Secretory Pathway*

It is proposed that the assembly of a Nef·MHC-I·adaptor protein 1 complex early in the secretory pathway is important for Nef activity.

HIV-1 Nef disrupts MHC-I trafficking by recruiting AP-1 to the MHC-I cytoplasmic tail

Evidence suggests that binding of AP-1 to the Nef–MHC-I complex is an important step required for inhibition of antigen presentation by HIV.

Human immunodeficiency virus-1 Nef expression induces intracellular accumulation of multivesicular bodies and major histocompatibility complex class II complexes: potential role of phosphatidylinositol 3-kinase.

It is shown that Nef modifies major histocompatibility complex class II (MHC II) intracellular trafficking and thereby its function, and induces an increase of the number of MVBs where MHC II complexes accumulate.

HIV-1 Nef sequesters MHC-I intracellularly by targeting early stages of endocytosis and recycling

The importance of the early stages of the endocytic network in the removal of MHC-I from the cell surface and its re-localization within the cell, which allows HIV-1 to optimally evade host immune responses, is demonstrated.

The Role of the Nef Protein in MHC-I Downregulation and Viral Immune Evasion by HIV-1

This review will examine how the multifunctional Nef protein can mediate downregulation of the Major Histocompatibility Complex (MHC) I proteins from the surface of infected cells as a means of immune evasion by HIV.

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

HIV-1 Nef-mediated endocytosis of MHCII provides a novel perspective on the regulation of normal MHC II trafficking as well as mechanisms involved in normal M HCII recycling and turnover to mediate the delivery of cell surface MHCii to a lysosomal destination.



Reduced cell surface expression of processed human immunodeficiency virus type 1 envelope glycoprotein in the presence of Nef

The intracellular accumulation of fully processed envelope glycoproteins could significantly delay the cytopathic effect associated with envelope surface expression in HIV-infected cells and may be relevant to the selective advantage associated with Nef during the in vivo infectious process.

Human immunodeficiency virus type 1 Nef induces accumulation of CD4 in early endosomes

In the presence of Nef, CD4 accumulated in acidic intracellular vesicles that were not stained by antibodies against rab6, a marker of the Golgi apparatus complex, showing that CD4 was trapped in early endosomes, without significant accumulation of CD4 in late endocytic compartments.

Major histocompatibility complex class I molecules internalized via coated pits in T lymphocytes

It is shown that class I molecules are differentially regulated in T and B lymphocytes and fibroblasts, and the endocytic pathway in T lymphocytes is similar to those of other more classical cell-surface receptors involved in receptor-mediated endocytosis.

Virus-induced loss of class I MHC antigens from the surface of cells infected with myxoma virus and malignant rabbit fibroma virus.

It is proposed that such a major perturbation of the class I MHC complex would likely downregulate theclass I-mediated presentation of viral Ag required to initiate cell-mediated immunity to these viruses.

Down-modulation of MHC-I in a CD4+ T cell line, CEM-E5, after HIV-1 infection.

Radioimmunoprecipitation of M HC-I protein from CEM-E5 indicated that the decrease of surface MHC-I is caused by decreased total protein secondary to a decrease in the level of mRNA for MHC -I, which is related to down-regulation during the time periods examined.

Human immunodeficiency virus type 1 Nef increases the efficiency of reverse transcription in the infected cell

The data suggest that the expression of Nef in virus-producing cells is required for efficient processing of the early stages of virus replication in target cells, including the internalization in an appropriate cell compartment and the uncoating of the particle.

Human cytomegalovirus down-regulates HLA class I expression by reducing the stability of class I H chains.

It is concluded that HCMV reduces human MHC class I protein levels by interference with the stability of class I H chains, regardless of their association with beta 2m.

Serine phosphorylation-independent downregulation of cell-surface CD4 by nef

A Moloney murine leukaemia virus-based retroviral vector is used in order to express the nef gene of HIV-1 in three lymphocytic cell lines expressing CD4, and it is found that cell-surface CD4 expression is inversely related to nef expression.

Downregulation of HLA class I antigens in HIV-1-infected cells.

It is reported that in CD4+ HeLa cells, in H9 cells, and in peripheral T lymphocytes HLA class I antigens are downregulated following infection with HIV-1, effected at a posttranscriptional level.

Altered T cell activation and development in transgenic mice expressing the HIV‐1 nef gene.

The observations from transgenic mice suggest that nef‐elicited perturbations in T cell signalling play an important role in the viral life cycle in vivo, perhaps resulting in elimination of infected CD4+ T cells.