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Therapeutic targeting of HCMV-encoded chemokine receptor US28: Progress and challenges
Christian Berg1, Mette M Rosenkilde1
1Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract:
The pervasive human cytomegalovirus (HCMV) causes significant morbidity in immunocompromised individuals. Treatment using the current standard-of-care (SOC) is limited by severe toxic adverse effects and anti-viral resistance development. Furthermore, they only affect HCMV in its lytic phase, meaning viral disease is not preventable as latent infection cannot be treated and the viral reservoirs persist. The viral chemokine receptor (vCKR) US28 encoded by HCMV has received much attention in recent years. This broad-spectrum receptor has proven to be a desirable target for development of novel therapeutics through exploitation of its ability to internalize and its role in maintaining latency. Importantly, it is expressed on the surface of infected cells during both lytic and latent infection. US28-targeting small molecules, single-domain antibodies, and fusion toxin proteins have been developed for different treatment strategies, e.g. forcing reactivation of latent virus or using internalization of US28 as a toxin shuttle to kill infected cells. These strategies show promise for providing ways to eliminate latent viral reservoirs and prevent HCMV disease in vulnerable patients. Here, we discuss the progress and challenges of targeting US28 to treat HCMV infection and its associated diseases.
Insights
Human cytomegalovirus (HCMV) infection poses risks to immunocompromised individuals. Targeting the US28 viral chemokine receptor offers a promising strategy to combat both lytic and latent HCMV, addressing limitations of current treatments.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- Human cytomegalovirus (HCMV) causes significant illness in immunocompromised patients.
- Current standard-of-care (SOC) treatments for HCMV are limited by toxicity, resistance, and inability to treat latent infections.
- Latent HCMV reservoirs persist, contributing to viral disease and making prevention difficult.
Purpose of the Study:
- To explore the potential of targeting the HCMV-encoded viral chemokine receptor US28 as a therapeutic strategy.
- To review the progress and challenges associated with developing US28-targeting treatments.
- To discuss novel therapeutic approaches for eliminating latent HCMV reservoirs.
Main Methods:
- Review of existing literature on HCMV, US28, and therapeutic strategies.
- Analysis of US28's role in HCMV latency and its potential as a drug target.
- Discussion of various US28-targeting modalities, including small molecules, antibodies, and fusion toxins.
Main Results:
- The US28 receptor is expressed during both lytic and latent HCMV infection, making it a viable target.
- US28's internalization capability and role in latency present opportunities for therapeutic intervention.
- Development of US28-targeting agents shows promise for eliminating latent viral reservoirs.
Conclusions:
- Targeting the US28 viral chemokine receptor represents a promising avenue for novel HCMV therapeutics.
- Strategies involving US28 can potentially address limitations of current SOC treatments, including latent infection.
- Further research and development are needed to overcome challenges in translating US28-targeting therapies into clinical practice.
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