Essay: US28 HCMV (Human Cyto-Megalo Virus) encoded vGPCR (Page 2 of 2)

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US28 is one of four HCMV (Human Cyto-Megalo Virus) encoded vGPCRs that has been extensively studied over the years. It exhibits high constitutive activity and posseses the ability to bind ligands from two separate chemokine classes. The subsequent distinct signalling pathways are initated upon G-protein activation and interestingly, dependent on the type (or the absence) of bound ligand. The functional consequences of US28 and the signalling pathways have been proposed to mediate various diseases such as cardiovascular diseases and tumorigenesis. US28 has also been proposed to act as a co-receptor for HIV-1 (Human Immunodeficiency Virus) entry in CD4+ coexpressing cells. US28 thus becomes an important pharmacological target in combating HCMV associated diseases. This review will focus on the general binding, signalling and regulation of US28, their functional consequences in mediating diseases and most importantly, the potential of using small molecules and FTP (Fusion-Toxicity-Proteins) in ameliorating HCMV-associated diseases and preventing life-threatening states for immunocompromised individuals. The underlying articles for this review has been gathered either by using MeSH (Medical Subject Headings) search terms or direct search terms in PubMed on NCBI’s (National Center for Biotechnology Information) website.

HCMV is a fairly common β-virus that lies latent throughout the life of the typical, healthy human being [1]. Normally, clinical manifestations are not present unless the infected individual is immunocompromised such as in AIDS-, cancer-, and transplant- patients and in neonates, whom as a result can end up in severe or even fatal states [2]. Furthermore, HCMV has been linked to the development of cardiovascular diseases, for instance atherosclerosis, restenosis after angioplasty, and vascular sclerosis in transplants (“associated with chronic rejection of transplanted solid organs”) [1]. An association between HCMV and tumorigenesis and HIV-progression has also been clearly established [3, 4].

HCMV encodes four vGPCRs, US27, US28, UL33 and UL78 [5]. All of these vGPCRs show high homology to chemokine receptors existent endogenously in mammalians, and subsequently, they bind to chemokines and interfere with chemokine signalling and thus conflict with the host’s chemokine and immune system. Among the four vGPCRs, US28 is the most extensively studied due to its high ligand, independent constitutive activation of phospholipase C and NF-kB as well as its ability to bind both CC-chemokines (e.g. RANTES and MCP-1 ) and CX3C-chemokines (Fractalkine) [5].

The functional consequence of both of these characteristics, high constitutive activity and binding of different chemokines, are factors that are involved in the development of the various HCMV-associated diseases [1, 5]. Lastly, US28 acts as a chemokine scavenger receptor through its ability to undergo constitutive internalization, which combined with its constitutive regulation of signalling, ultimately augments viral dissemination [6, 7].

In light of the functional, pathophysiological significance of US28, it’s cognate signalling pathways and regulation/internalization, targeting US28 with small molecule variants of VUF2774 as well as the FTP-variant, F49A-FTP, may have a profound impact in treating HCMV and thus in preventing life-threatening, HCMV-associated diseases in immunocompromised patients.

Material & Method

The articles used in the writing of this review has mainly been found using MeSH search terms, which is an “NLM [National Library of Medicine] controlled vocabulary thesaurus used for indexing articles for PubMed”[8] on NCBI’s website. Since US28 is a fairly narrow topic, a search using MeSH merely yielded a total of 82 articles. After having completed the synopsis in guidance with the bachelor supervisor combined with reading some reviews to gather background knowledge, the articles were found by taking one topic at a time. The articles were then picked after relevance, article type (mainly original articles) and publishing year (after the year 2000):

Generally about US28:

To acquire a general understanding of US28, reviews were the first articles that were searched for.

Using MeSH search terms “US28” and filtering with “reviews” (US28 receptor, Cytomegalovirus”[Supplementary Concept] AND Review[ptyp]), 7 articles were found. The article “Human Cytomegalovirus US28: a functionally selective chemokine binding receptor” was selected because of relevance (favoured words such as: “Human Cytomegalovirus”, “US28”, “chemokine”, “Binding”, “Receptor”.) as well as not being too specific. The publishing year was 2001, and thus after 2000.

To find another general review I searched directly on PubMed’s database, which yielded 20 articles with the same search profile as above. “US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection.” was selected again because of its general article title, relevance (“US28”, “Human cytomegalovirus”, “Antiviral”) and lastly the recent year of publishing, 2017.

Upon reading the reviews, a greater, general understanding of US28 was acquired. This allowed for a more specific search profile for the following topics:

Ligand binding and signalling

• MeSH search terms: “US28 receptor “, “Protein binding”, “GTP-protein binding”, “Type C phospholipases”, “signal transduction”.

• Number of hits: 5-10 articles

• Favoured words: “binding”, “Chemokine receptor”, “signalling”, “constitutive activity”, “phospholipase”

• Additional:

o General mechanism of binding and signalling was favoured.

Regulation and internalization/recycling

• MeSH search terms/ filter: “US28 receptor “, “Beta arrestins”, “Internalization”.

• Number of hits: 3 articles

• Favoured words: “Internalization, Beta arrestins” and “regulation”.

• Additional:

o General mechanism of regulation and internalization was favoured.

Pathophysiological relevance of US28

Cardiovascular disease

• MeSH search terms: “US28 receptor and “Smooth muscle”.

• Number of hits: 6 articles

• Favoured words: “Migration/motility”, “chemokine receptor”.

• Additional

o Since the search term “Cardiovascular disease” in combination yielded 0 original articles, the term “smooth muscle” was used instead; an underlying factor for US28-mediated cardiovascular disease.

o Since “migration/motility” appeared twice out of the 6 hits, the most recent article with the most recent publishing year was chosen (2009)


• MeSH search terms”US28 receptor and “carcinogenesis”/”Neoplasms”

• Number of hits: 4-10

• Favoured words: “Tumor/Tumorigenesis, “Cancer”, “angiogenesis”, “proliferation”

• Additional

o The more general mechanisms of tumorigenesis were used as criteria, thereby filtering away the articles that were more specific to a certain type of cancer (However, colorectal cancer article [9] was picked as an example due to its incidence rate as well as publishing year [2016]).

US28 as pharmacological target

Small molecules:

• MeSH search terms: “US28 receptor”, “small molecules”, “drug inverse agonism”, “drug design”,

• Number of hits: 1-10

• Favoured words: “Inverse agonism”, “Small molecules”, “modulate”

• Additional

o Articles about VUF2774 and VUF2774 variants were favoured.

FTP (Fusion Toxicity Protein)

• PubMed search terms: “US28 toxin protein”

• Number of hits: 5 hits

• Favoured words: “Toxin protein”

• Additional:

o Searching directly in PubMed was carried because there were either no MeSH terms for FTP/ toxin protein or no hits appeared. This was no problem (in terms of too many hits) since targeting US28 with FTP is a relatively new principle.

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