The Human Cytomegalovirus Chemokine vCXCL-1 Modulates Normal Dissemination Kinetics of Murine Cytomegalovirus
            <i>In Vivo</i>

Jackson, Joseph W.; Hancock, Trevor J.; LaPrade, Ellen; Dogra, Pranay; Gann, Eric R.; Masi, Thomas; Panchanathan, Ravichandran; Miller, William E.; Wilhelm, Steven W.; Sparer, Tim E.

doi:10.1128/mbio.01289-19

Cited by 10 publications

(12 citation statements)

References 62 publications

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“…Conversely, old world NHP CMVs encode five to seven UL146 homologs. Since 68–1 lacks these highly expressed genes, they are not required for the establishment and maintenance of persistent infection but it is possible that these chemokine homologs support viremia and dissemination during primary infection or upon re-infection, a possibility reinforced by the recent observation that inserting the HCMV UL146 protein into MCMV significantly enhances virus dissemination kinetics in infected mice [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome

et al. 2020

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Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the only available RhCMV clone that permits genetic modifications is based on the 68–1 strain which has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptations. As a result, 68–1 displays reduced viremia in RhCMV-naïve animals and limited shedding compared to non-clonal, low passage isolates. To overcome this limitation, we used sequence information from primary RhCMV isolates to construct a full-length (FL) RhCMV by repairing all mutations affecting open reading frames (ORFs) in the 68–1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naïve RM with the reconstituted virus resulted in significant viremia in the blood similar to primary isolates of RhCMV and furthermore led to high viral genome copy numbers in many tissues at day 14 post infection. In contrast, viral dissemination was greatly reduced upon deletion of genes also lacking in 68–1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68–1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome

et al. 2020

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“…Since 68-1 lacks these highly expressed genes, they are not required for the establishment and maintenance of persistent infection but it is possible that these chemokine homologs support viremia and dissemination during primary infection or upon re-infection, a possibility reinforced by the recent observation that inserting the HCMV UL146 protein into MCMV significantly enhances virus dissemination kinetics in infected mice (60).…”

Section: Discussionmentioning

confidence: 99%

In vitroandin vivocharacterization of a recombinant rhesus cytomegalovirus containing a complete genome

Taher

Mahyari

Kreklywich

et al. 2020

Preprint

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In vitro and in vivo characterization of a recombinant1 rhesus cytomegalovirus containing a complete genome 2 3 Abstract (300 words) 42 Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species 43 specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models 44 using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has 45 been established as a representative model for infection of humans with HCMV due to the close 46 evolutionary relationships of both host and virus. However, the commonly used 68-1 strain of 47 RhCMV has been passaged in fibroblasts for decades resulting in multiple genomic changes due 48 to tissue culture adaptation that cause reduced viremia in RhCMV-naïve animals and limited 49 shedding compared to low passage isolates. Using sequence information from primary RhCMV 50 isolates we constructed a full-length (FL) RhCMV by repairing all presumed mutations in the 68-51 1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naïve 52 RM with the reconstituted virus resulted in significant replication in the blood similar to primary 53 isolates of RhCMV and furthermore led to extensive viremia in many tissues at day 14 post 54 infection. In contrast, viral dissemination and viremia was greatly reduced upon deletion of genes 55 also lacking in 68-1. Transcriptome analysis of infected tissues further revealed that chemokine-56 like genes deleted in 68-1 are among the most highly expressed viral transcripts both in vitro and 57 in vivo consistent with an important immunomodulatory function of the respective proteins. We 58 conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while 59 being amenable to genetic modifications through BAC recombineering techniques.60 61 4 Author Summary (150-200 word non-technical summary) 62 Human cytomegalovirus (HCMV) infections are generally asymptomatic in healthy 63 immunocompetent individuals, but HCMV can cause serious disease after congenital infection and 64 in individuals with immunocompromised immune systems. Since HCMV is highly species specific 65 and cannot productively infect immunocompetent laboratory animals, experimental infection of 66 rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a closely related 67 animal model for HCMV. By employing the unique ability of CMV to elicit robust and lasting 68 cellular immunity, this model has also been instrumental in developing novel CMV-based vaccines 69 against chronic and recurring infections with pathogens such as the human immunodeficiency 70 virus (HIV) and Mycobacterium tuberculosis (Mtb). However, most of this work was conducted 71 with derivatives of the 68-1 strain of RhCMV which has acquired multiple genomic alterations in 72 tissue culture. To model pathogenesis and immunology of clinical HCMV isolates we generated a 73 full-length (FL) RhCMV clone representative of low passage isolates. Infection of RhCMV-naïve 74 RM with FL-...

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“…The anti-viral activity of these peptides in HS-deficient MCMV target cells has not been tested yet; however, our results suggest they might be ineffective in macrophages. Macrophages, monocytes, neutrophils and dendritic cells have been reported to be some of the cell types that MCMV infects first and hijacks for its dissemination to distal organs [63][64][65][66]. In these cell types, CS is the most abundant surface GAG, and their HS levels range from low (macrophages, monocytes and dendritic cells) to non-detectable (neutrophils) [53,67,68], which suggests that anti-HS peptides would have a poor anti-MCMV effect in these cells.…”

Section: Discussionmentioning

confidence: 99%

Mouse Cytomegalovirus Differentially Exploits Cell Surface Glycosaminoglycans in a Cell Type-Dependent and MCK-2-Independent Manner

Pontejo

Murphy

2019

Viruses

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Many viruses initiate interaction with target cells by binding to cell surface glycosaminoglycans (GAGs). Heparan sulfate (HS) appears to be particularly important in fibroblasts, epithelial cells and endothelial cells, where it represents the dominant GAG. How GAGs influence viral infectivity in HS-poor target cells such as macrophages has not been clearly defined. Here, we show that mouse cytomegalovirus (MCMV) targets HS in susceptible fibroblasts and cultured salivary gland acinar cells (SGACs), but not in macrophage cell lines and primary bone marrow-derived macrophages, where chondroitin sulfate was the dominant virus-binding GAG. MCK-2, an MCMV-encoded GAG-binding chemokine that promotes infection of macrophages as part of a gH/gL/MCK-2 entry complex, was dispensable for MCMV attachment to the cell surface and for direct infection of SGACs. Thus, MCMV tropism for target cells is markedly influenced by differential GAG expression, suggesting that the specificity of anti-GAG peptides now under development as HCMV therapeutics may need to be broadened for effective application as anti-viral agents.

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The Human Cytomegalovirus Chemokine vCXCL-1 Modulates Normal Dissemination Kinetics of Murine Cytomegalovirus In Vivo

Cited by 10 publications

References 62 publications

In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome

In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome

In vitroandin vivocharacterization of a recombinant rhesus cytomegalovirus containing a complete genome

Mouse Cytomegalovirus Differentially Exploits Cell Surface Glycosaminoglycans in a Cell Type-Dependent and MCK-2-Independent Manner

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