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Review
. 2019 Jul 24;20(15):3626.
doi: 10.3390/ijms20153626.

Battle between Host Immune Cellular Responses and HCMV Immune Evasion

Trishna Manandhar  1 , Gia-Gia T Hò  1 , Wiebke C Pump  1 , Rainer Blasczyk  1 , Christina Bade-Doeding  2
Affiliations
Review

Battle between Host Immune Cellular Responses and HCMV Immune Evasion

Trishna Manandhar et al. Int J Mol Sci. .

Abstract

Human cytomegalovirus (HCMV) is ubiquitously prevalent. HCMV infection is typically asymptomatic and controlled by the immune system in healthy individuals, yet HCMV can be severely pathogenic for the fetus during pregnancy and in immunocompromised persons, such as transplant recipients or HIV infected patients. HCMV has co-evolved with the hosts, developed strategies to hide from immune effector cells and to successfully survive in the human organism. One strategy for evading or delaying the immune response is maintenance of the viral genome to establish the phase of latency. Furthermore, HCMV immune evasion involves the downregulation of human leukocyte antigens (HLA)-Ia molecules to hide infected cells from T-cell recognition. HCMV expresses several proteins that are described for downregulation of the HLA class I pathway via various mechanisms. Here, we review the wide range of immune evasion mechanisms of HCMV. Understanding the mechanisms of HCMV immune evasion will contribute to the development of new customized therapeutic strategies against the virus.

Keywords: HCMV; immune evasion mechanisms; immune surveillance mechanisms; virus–host interaction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Human cytomegalovirus (HCMV) life cycle. HCMV enters the cell through interaction of the host receptors with specific viral glycoproteins. Capsid and tegument proteins are release into the host cytosol. The capsid releases the viral genome into the nucleus, leading to the expression of immediate early (IE) genes. The IE proteins activate the expression of the early (E) genes. The E proteins initiate viral genome replication and the expression of late (L) genes. The L gene expression initiates the capsid assembly and the expression of tegument- and glycoproteins. The genome-loaded capsid enters the cytosol via nuclear egress. The capsid associates with the tegument proteins. The capsid acquires the viral envelope by budding into intracellular vesicles. The enveloped viral particles are released into the extracellular space.
Figure 2
Figure 2
HCMV-mediated downregulation of HLA-class I pathway. The protein pp65 prevents the presentation of IE-derived peptides. Glycoprotein unique short 2 (gpUS2) and US11 (gpUS11) redirect HLA class I heavy chain (hc) from the endoplasmic reticulum (ER) to the cytosol and induce the proteasomal degradation of the molecule. Glycoprotein US6 (gpUS6) inhibits the function of transporter associated with antigen processing (TAP). Glycoprotein US3 (gpUS3) inhibits the tapasin-dependent peptide loading and retains HLA class I molecules in the endoplasmic reticulum (ER). Glycoprotein US10 (gpUS10) retains HLA class I hc in the ER. gpUS10 and gpUS2 induce degradation of HLA-G.
Figure 3
Figure 3
HCMV-mediated up-regulations of the ligands for natural killer (NK) cell inhibitory receptors. The signal peptide of unique long (UL)40 (gpUL40) up-regulate the surface expression of HLA-E. HLA-E is a ligand for the NK cell inhibitory receptor CD94/NKG2A. The HLA class I homologue, gpUL18, inhibits the NK cell activity by inducing NK cell inhibitory receptor LIR1 (ILT2).
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