TY - JOUR

T1 - Therapeutic targeting of HCMV-encoded chemokine receptor US28

T2 - Progress and challenges

AU - Berg, Christian

AU - Rosenkilde, Mette M.

N1 - Publisher Copyright: Copyright © 2023 Berg and Rosenkilde.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - drug development

KW - fusion toxin protein

KW - HCMV (human cytomegalovirus)

KW - single-domain antibodies (sdAb)

KW - small molecule

KW - targeting

KW - US28

KW - viral chemokine receptor

UR - http://www.scopus.com/inward/record.url?scp=85149402340&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2023.1135280

DO - 10.3389/fimmu.2023.1135280

M3 - Review

C2 - 36860859

AN - SCOPUS:85149402340

VL - 14

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 1135280

ER -