Modulating Immune Responses in Human Cytomegalovirus: Implications for Disease Progression and Therapy

Human cytomegalovirus (HCMV) is the leading infectious cause of congenital birth defects. Indeed, 3 out of 10 babies born each day will have long-term problems resulting from HCMV infection. Additionally, HCMV infection causes severe disease in individuals who are immunosuppressed following an organ transplant or living with HIV/AIDS. There is no currently licensed vaccine against HCMV, and existing antivirals have problems due to toxicity and the development of resistance.

HCMV is a paradigm of viral immune evasion. The majority of its genome is dispensable for growth in cell culture systems and is predicted to encode immune evasion genes:

1. gpUL4: A heavily glycosylated protein secreted by HCMV-infected cells binds to TRAIL (TNF-related apoptosis-inducing ligand) with high affinity, acting as a decoy receptor and inhibits TRAIL-mediated apoptosis of target cells. gpUL4 suppresses NK cell degranulation (measured by CD107a mobilization) in a dose-dependent manner when added to assays with NK cells and target cells. Thus gpUL4 can inhibit NK cell responses to other viruses like SARS-CoV-2

2. HCMV gene UL148 is necessary and sufficient to suppress the surface expression of CD58 on infected cells. UL148 causes intracellular retention of CD58. Deleting UL148 from HCMV restores CD58 expression and enhances the recognition of infected cells by HCMV-specific CTLs

3. Four US12 family members (US12, US14, US18, US20) help HCMV evade NK cell recognition. US18 and US20 work together to suppress the expression of B7-H6, an important NK cell-activating ligand

4. LIR-1 (Leukocyte Immunoglobulin-like Receptor-1) is a cellular receptor that binds to the human cytomegalovirus (HCMV) UL18 protein and cellular MHC class I molecules. The interaction between UL18 and LIR-1 may represent a viral immune evasion strategy.

   
   

   Conclusion

    The lack of a licensed vaccine and the limitations of current antiviral therapies underscores the urgent need for new preventive and therapeutic strategies. HCMV's extensive repertoire of immune evasion mechanisms, including its ability to modulate NK cell and cytotoxic T lymphocyte (CTL) responses, highlights its evolutionary sophistication in escaping host immune detection. Viral proteins like gpUL4, UL148, US12 family members, and UL18 play critical roles in suppressing immune recognition and response, allowing HCMV to establish persistent infection. By understanding these immune evasion strategies, future research can better target the viral elements responsible for immune escape, providing pathways for developing more effective therapies and vaccines.

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