Sequencing Directly from Clinical Specimens Reveals Genetic Variations in HCMV-Encoded Chemokine Receptor US28 That May Influence Antibody Levels and Interactions with Human Chemokines

Abstract

Human cytomegalovirus (HCMV) is a common viral pathogen of solid organ transplant recipients, neonates, and HIV-infected individuals. HCMV encodes homologs of several host genes with the potential to influence viral persistence and/or pathogenesis.

Variants of HCMV UL18 Sequenced Directly from Clinical Specimens Associate with Antibody and T-Cell Responses to HCMV

“…In this study, we identify nonsynonymous variants in the UL18 gene by sequencing HCMV directly from clinical samples. Compared to our analyses of US28 and UL111a in the same samples [ 29 , 35 ], UL18 had a higher amount of variation. Several variations were donor group specific, but eight were present in all cohorts and all sample types.…”

“…Many publications examining HCMV diversity are based on Sanger sequencing of PCR amplicons, which may miss mixed infections [ 27 , 28 , 29 ]. Some studies have used HCMV propagated in vitro which may miss strains present only in vivo.…”

Therapeutic targeting of HCMV-encoded chemokine receptor US28: Progress and challenges

“…The US28 gene in contrast is quite conserved, strengthening its position as a therapeutic target ( 67 ). However, various genotypes have been observed ( 71 – 73 ), notably some with marked differences in the N-terminal (extracellular) tail of the receptor, which is important for chemokine binding. Indeed, molecular modeling has predicted changes in binding affinities of several endogenous chemokines to US28 variants ( 73 ).…”

“…However, various genotypes have been observed ( 71 – 73 ), notably some with marked differences in the N-terminal (extracellular) tail of the receptor, which is important for chemokine binding. Indeed, molecular modeling has predicted changes in binding affinities of several endogenous chemokines to US28 variants ( 73 ). Variations of extracellular loops (ECLs) and the C-terminal (intracellular) tail have also been observed and, albeit less extensive, are not to be overlooked for their potential to alter US28 signaling.…”

“…Variations of extracellular loops (ECLs) and the C-terminal (intracellular) tail have also been observed and, albeit less extensive, are not to be overlooked for their potential to alter US28 signaling. While the mechanism and biological significance are unclear, one study reported an increase in anti-CMV antibodies of renal transplant recipients carrying R267K-US28 ( 73 ). Additionally, antibody levels were reduced in HIV infected individuals carrying D170N-US28 and were accompanied by an increased HIV viral load and a reduction in sIFN-α/βR levels 12 months post initiation of anti-retroviral therapy ( 73 ).…”