Herpes Simplex Virus Type 1 Targets the MHC Class II Processing Pathway for Immune Evasion

Abstract

HSV type 1 (HSV-1) has evolved numerous strategies for modifying immune responses that protect against infection. Important targets of HSV-1 infection are the MHC-encoded peptide receptors. Previous studies have shown that a helper T cell response and Ab production play important roles in controlling HSV-1 infection. The reduced capacity of infected B cells to stimulate CD4+ T cells is beneficial for HSV-1 to evade immune defenses. We investigated the impact of HSV-1 infection on the MHCII processing pathway, which is critical to generate CD4+ T cell help. HSV-1 infection targets the molecular coplayers of MHC class II processing, HLA-DR (DR), HLA-DM (DM), and invariant chain (Ii). HSV-1 infection strongly reduces expression of Ii, which impairs formation of SDS-resistant DR-peptide complexes. Residual activity of the MHC class II processing pathway is diminished by viral envelope glycoprotein B (gB). Binding of gB to DR competes with binding to Ii. In addition, we found gB associated with DM molecules. Both, gB-associated DR and DM heterodimers are exported from the endoplasmic reticulum, as indicated by carbohydrate maturation. Evaluation of DR, DM, and gB subcellular localization revealed abundant changes in intracellular distribution. DR-gB complexes are localized in subcellular vesicles and restrained from cell surface expression.

Effects of Herpes Simplex Virus Amplicon Transduction on Murine Dendritic Cells

“…This observation is in line with the result that glycoprotein B (gB) on the viral envelope restrained the surface expression of MHCII by associating with the HLA-DR subunit (Neumann et al, 2003). gB prevented cell surface expression of MHCII and caused significant changes in MHCII intracellular distribution (Neumann et al, 2003). A similar scenario could be envisioned for the effect observed in iDCs transduced with amplicon virions if virion envelope-localized gB mediates this phenomenon, as differentiation between the effects of gB harbored in the envelope of incoming virions and gB expressed de novo during infection was not made by this prior study.…”

“…4C, right), we assumed that the majority of CD11c þ MHCII þ (R3) cells began to lose their surface expression of MHCII and became positive only for CD11c (R5) after amplicon transduction. This observation is in line with the result that glycoprotein B (gB) on the viral envelope restrained the surface expression of MHCII by associating with the HLA-DR subunit (Neumann et al, 2003). gB prevented cell surface expression of MHCII and caused significant changes in MHCII intracellular distribution (Neumann et al, 2003).…”

The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein

“…It has been demonstrated that ICP47 blocks antigen presentation via MHC-I (12,13). ICP22 and gB of HSV-1 interrupt MHC-II-dependent antigen presentation by B cells (14,15). We also observed that ICP34.5 interferes with dendritic cell maturation, resulting in the inhibition of T cell activation (16).…”

The Herpes Simplex Virus-1 Encoded Glycoprotein B Diverts HLA-DR into the Exosome Pathway

“…The following mouse mAbs 2c/2 (anti-gB; IgG2a), 10B7 (anti-gB; IgG1), L243 (anti-DR; IgG2a), ISCR3 (anti-DR; IgG2b), TAL-1B5 (anti-DRa; IgG1), LGII-612.14 (anti-HLA-DR, -DP, and -DQ; IgG1), Bu43 (anti-Ii; IgM), clone 37 (BD Bioscience, Heidelberg, Germany; anti-calnexin; IgG1), and FK2 (anti-ubiquitin; IgG1; kindly provided by Dr. J. Höhfeld, University of Bonn, Bonn, Germany) were used in this study (7,12,13). Anti-DR-Alexa 700 (clone MEM-12) and anti-CD63-Alexa 488 (clone MEM-259) Abs were purchased from Exbio (Vestec, Czech Republic).…”

“…We recently discovered that during HSV-1 infection of B lymphocytes, the viral glycoprotein B (gB) targets the MHCII processing pathway (7).…”