Insight for Immunotherapy of HCMV Infection

Abstract

Human cytomegalovirus (HCMV), a ubiquitous in humans, has a high prevalence rate. Young people are susceptible to HCMV infection in developing countries, while older individuals are more susceptible in developed countries. Most patients have no obvious symptoms from the primary infection. Studies have indicated that the virus has gradually adapted to the host immune system. Therefore, the control of HCMV infection requires strong immune modulation. With the recent advances in immunotherapy, its application to HCMV infections is receiving increasing attention. Here, we discuss the immune response to HCMV infection, the immune escape mechanism, and the different roles that HCMV plays in various types of immunotherapy, including vaccines, adoptive cell therapy, checkpoint blockade therapy, and targeted antibodies.

Keywords: human cytomegalovirus; immune escape mechanism; immune response; immunotherapy; infection.

Figure 1

The immune modulation induced by HCMV. HCMV entry into the infected cells through the interaction of the trimeric gH/gL/gO complex (TC) with PDGFRα or the binding of the pentameric gH/gL/UL128-131 complex (PC) with Nrp2, etc. There are multiple strategies for the HCMV to achieve immune escape. For instance, US7 and US8 bind both TLR3 and TLR4, facilitating receptor destabilization by distinct mechanisms; US11 inhibits the assembly of FcRn with β2m resulting in the retention of FcRn in the endoplasmic reticulum, consequently blocking FcRn trafficking to the endosome; UL16, UL142 bind to ligands for NKG2D, the natural killer cell-activating receptor; UL18, US6 interfere with the physical association between MHC class I molecules and TAP; US18, US20 downregulation of B7-H6 leads to evasion from NKp30-mediated killing; US21 protein is a viral-encoded ion channel that regulates intracellular Ca²⁺ homeostasis and protects cells against apoptosis; UL26 downregulates the expression of antiviral genes; UL82 inhibits STING-mediated signaling; UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112; UL145 hijacks Cullin4 to invoke HLTF; miR-UL22A and miR-US5-2 suppress the secretion of TGF-β; gp68, gP34, gpRL13 and gP95 bind to the Fc segment of IgG on the membrane, resulting in the inability of FcγRⅢA receptor on effector cells to bind to the antibody on the target cells and hinder the communication or cross talk between cellular immunity and humoral immunity.

Figure 2

The current prevention and therapy strategies for HCMV infection. With respect to vaccines to prevent HCMV infection, inactivated virus (e.g., Towne, Toledo) weakened by a series of in vitro subcultures and subunit vaccines (e.g., gB/MF59), DNA vaccines (e.g., CMVPepVax, e.g., CMVPepVax, Chimeras, ASP0133, VCL-CB01), have been developed. When these vaccines are injected in the body, they can activate lymphocytes to kill the infected cell antigen-presenting cells (e.g., dendritic cells, macrophages, monocytes). A classic common antiviral inhibitor (cidofovir, ganciclovir, etc.) is a nucleotide analog that mainly impedes the DNA of HCMV synthesis. The target of checkpoint blockade therapy and targeted antibodies in HCMV infection is still under research. HCMV, as an oncolytic virus, usually infects tumor cells and creates an inflammatory microenvironment by causing infected cells to express molecules that target antigenic determinants and recruit immune cells (such as T lymphocytes, macrophages, monocytes, etc.) to cause infected cell apoptosis. ATC involves extraction of PBMC from the body, isolation of target cells (such as T lymphocytes and NK cells) in vitro genetic modification to immunotherapy cells, including HCMV-specific T cells, TCR-T cells, CAR-T cells, and then multiplication, and finally reinfusion into the body.