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

Abstract

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 lymphocytes. We have observed that this phenomenon depends on the expression of Nef. nef is an early gene of primate lentiviruses, which is necessary for maintaining high virus loads and inducing AIDS. Nef is not necessary for viral replication in vitro and stimulates the endocytosis of CD4. We show that the expression of MHC-I at the surface of lymphoid, monocytic and epithelial cells was reduced in the presence of Nef protein from various HIV-1 strains. Whereas MHC-I protein synthesis and transport through the endoplasmic reticulum and cis Golgi apparatus occurred normally in Nef(+) cells, surface MHC-I molecules were rapidly internalized, accumulated in endosomal vesicles and were degraded. The stimulation of MHC-I endocytosis by Nef represents a previously undocumented viral mechanism for evading the immune response.

To kill or be killed: how HIV exhausts the immune system

“…72 HIV strategies to protect lymphocytes from apoptosis include: (1) the upregulation of Bcl-2 and downmodulation of Bax by Vpr; 81 (2) the promotion of cell cycle progression, and subsequent increased virus production, by Tat-dependent inhibition of p53 transcription; 82 (3) the downregulation by Nef and gp120 of expression of the CD4 receptor by infected cells, thereby preventing subsequent gp120-CD4-mediated apoptosis; [83][84][85] and (4) the downmodulation by Vpu and Nef of the expression of MHC class I molecules and the upregulation of CD95L expression on infected cells, a strategy that might function to protect infected cells from cytolysis by CTL or NK cells. 86,87 These in vitro data are in line with in vivo observations showing that, in lymph-node biopsies from HIV-infected humans and SIV-infected monkeys, productively infected cells are not apoptotic, indicating that they are relatively resistant to direct HIV-induced killing in vivo. 31 Collectively, these data indicate that HIV can manipulate cellular apoptotic machinery, destroying the immune system through the activation of apoptotic programs in lymphocytes, but ensuring viral survival by manipulating the apoptotic machinery to its advantage in infected cells.…”

“…Nef downmodulates the expression of MHC class I molecules and upregulates CD95L expression on infected cells, a strategy that may function to protect infected cells from cytolysis by CTL or NK cells. 115,116 Nef, gp120 and Vpu contribute to the downregulation of CD4 receptor on infected cells, preventing subsequent gp120-CD4-mediated apoptosis. [117][118][119] The relative resistance to direct HIV-induced killing of infected cells is confirmed by in vivo studies on lymph node biopsies from HIV þ individuals, showing that productively infected cells are not apoptotic, in contrast to uninfected cells.…”

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

“…For example, HIV-1 can increase cellular endocytosis of HLA molecules via nef 45,46 , limit HLA transcription and peptide processing via tat 47,48 and suppress TAP-mediated peptide transport into the endoplasmic reticulum 49 . Under selection pressure from the immune system, HIV-1 also mutates rapidly to evade cytotoxic T lymphocyte responses.…”

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…[7][8][9][10][11] Because residual HIV expression continues despite effective ART [12][13][14][15][16] and is required for viral rebound, HIV-infected cells should theoretically be targetable by a T cell therapeutic agent. Several mechanisms are thought to be responsible for the apparent failure of autologous cytotoxic T lymphocytes (CTLs) to clear reactivated cells in HIV-infected individuals: HIV evolution prior to ART quickly selects for CTL escape mutations; [17][18][19] HIV Nef mediates downregulation of major histocompatibility complex class I (MHC-I), 20,21 protecting HIV-infected cells from T cell receptor (TCR)-dependent CTL killing; and HIV-specific CTL responses may be limited by exhaustion 22,23 or peripheral immune tolerance. 24,25 Over the last decade, major advances have been made in engineering human T cells via introduction of chimeric antigen receptors (CARs) to enable specific lysis of pathogenic targets.…”