Coinfection of the immunocompromised but not the immunocompetent host by multiple human cytomegalovirus strains

Baldanti, Fausto; Sarasini, Antonella; Furione, Milena; Gatti, Marta; Comolli, Giuditta; Revello, Maria Grazia; Gerna, Giuseppe

doi:10.1007/s007050050410

Cited by 30 publications

(28 citation statements)

References 17 publications

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“…Notably, in accordance with this idea, multiple strains were observed to emerge over time in patients who underwent an episode of immunosuppression (3), and the correlation of the presence of multiple strains with high virus load and poor prognosis was observed with immunocompromised adults (11,21,43). Several studies reported a high percentage of adult individuals (3, 49), but not infants (5,50), carrying multiple viral strains. This difference between adult and pediatric patients may also indicate that multiple strains are acquired primarily through consecutive superinfections over time, rather than through a single infection with codisseminating strains, as we see no rationale that could explain why codissemination should affect pediatric patients with lower probability.…”

Section: Discussionsupporting

confidence: 50%

Frequent Coinfection of Cells Explains Functional In Vivo Complementation between Cytomegalovirus Variants in the Multiply Infected Host

Čičin‐Šain

Podlech

Messerle

et al. 2005

J Virol

118

114

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In contrast to many other virus infections, primary cytomegalovirus (CMV) infection does not fully protect against reinfection. Accordingly, clinical data have revealed a coexistence of multiple human CMV variants/ strains in individual patients. Notably, the phenomenon of multiple infection was found to correlate with increased virus load and severity of CMV disease. Although of obvious medical relevance, the mechanism underlying this correlation is unknown. A weak immune response in an individual could be responsible for a more severe disease and for multiple infections. Alternatively, synergistic contributions of variants that differ in their biological properties can lead to qualitative changes in viral fitness by direct interactions such as genetic recombination or functional complementation within coinfected host cells. We have addressed this important question paradigmatically with the murine model by differently designed combinations of two viruses employed for experimental coinfection of mice. Specifically, a murine cytomegalovirus (MCMV) mutant expressing Cre recombinase was combined for coinfection with a mutant carrying Cre-inducible green fluorescent protein gene, and attenuated mutants were combined for coinfection with wild-type virus followed by two-color in situ hybridization studies visualizing the replication of the two viruses in infected host organs. These different approaches concurred in the conclusion that coinfection of host cells is more frequent than statistically predicted and that this coinfection alters virus fitness by functional trans-complementation rather than by genetic recombination. The reported findings make a major contribution to our molecular understanding of enhanced CMV pathogenicity in the multiply infected host.

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Section: Discussionsupporting

confidence: 50%

Frequent Coinfection of Cells Explains Functional In Vivo Complementation between Cytomegalovirus Variants in the Multiply Infected Host

Čičin‐Šain

Podlech

Messerle

et al. 2005

J Virol

118

114

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“…This finding is consistent with previous data from analysis of unrelated HCMV strains [Chou, 1990;Baldanti et al, 1998a]. As expected for related HCMV genomes, Toledo-US F and Toledo-UK F showed identical RFLP profiles in each region examined.…”

Section: Restriction Fragment Length Polymorphism and Southern Blot Asupporting

confidence: 93%

“…A single viral strain (identical to that of the mother), however, has been reported in HCMV isolates from congenitally infected newborns [Baldanti et al, 1998a]. The recovery of endothelial cell-tropic viral variants from Toledo, AD169 and Towne strains was assayed in the past, showing that endothelial celltropic variants were apparently present in Toledo virus preparations only [MacCormac and Grundy, 1999]; however, the genomes of the endothelial-cell-tropic variant (Toledo-UK E ) and the parental strain were never compared.…”

Section: Discussionmentioning

confidence: 95%

“…This finding (confirmed both using HCMV DNA from the original viral stocks and after propagation of viruses in the laboratory) is not consistent with previous analyses of related HCMV clinical isolates or plaque-purified variants from a single parental strain. In fact, this technique was shown to readily differentiate epidemiologically unrelated HCMV isolates, whereas epidemiologically related isolates or plaque-purified variants from a single viral progenitor showed consistently identical RFLP profiles [Baldanti et al, 1998a;Revello et al, 2001]. In addition, RFLP analysis of PCR products was shown to allow detection of single viral variants represented at a proportion of <10% in a mixed viral population .…”

Section: Restriction Fragment Length Polymorphism and Southern Blot Amentioning

confidence: 96%

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Genomes of the endothelial cell‐tropic variant and the parental Toledo strain of human cytomegalovirus are highly divergent

Baldanti

Revello

Percivalle

et al. 2002

Journal of Medical Virology

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The low-passage Toledo strain of human cytomegalovirus (HCMV) and fresh clinical HCMV isolates have been reported to share the capacity to propagate efficiently in endothelial cell cultures. In the laboratory, however, repeated attempts to adapt the Toledo strain to growth in endothelial cells have been unsuccessful. Southern blot analysis of the entire viral genome and restriction length polymorphism analysis of multiple genome regions amplified by PCR demonstrated that the reported endothelial cell-tropic viral variant of the Toledo strain and the parental Toledo strain are highly divergent. In fact, the restriction profile of the genome of the endothelial cell-tropic variant seems highly distinct from that of the parental strain. In conclusion, the degree of dissimilarity between the two genomes suggests that the endothelial cell-tropic variant of the Toledo strain could have originated from a recombination event.

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“…However, the generation of laboratory strains of WT HCMV is problematic not only because clinical samples often contain multiple strains (27,(29)(30)(31)(32)(33)(34)(35)(36), but especially because genetic adaptations occur even during the early stages of passage in cell culture. Thus, most strains passaged in fibroblasts are mutated in 1 of 3 adjacent genes (UL128, UL130, and UL131A; collectively termed the UL128 locus, UL128L) whose products form a complex bound to glycoproteins gH and gL in the virion envelope (37)(38)(39)(40)(41)(42)(43).…”

Section: Introductionmentioning

confidence: 99%

Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication

Stanton¹,

Baluchova²,

Dargan³

et al. 2010

J. Clin. Invest.

242

375

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Human cytomegalovirus (HCMV) in clinical material cannot replicate efficiently in vitro until it has adapted by mutation. Consequently, wild-type HCMV differ fundamentally from the passaged strains used for research. To generate a genetically intact source of HCMV, we cloned strain Merlin into a self-excising BAC. The Merlin BAC clone had mutations in the RL13 gene and UL128 locus that were acquired during limited replication in vitro prior to cloning. The complete wild-type HCMV gene complement was reconstructed by reference to the original clinical sample. Characterization of viruses generated from repaired BACs revealed that RL13 efficiently repressed HCMV replication in multiple cell types; moreover, RL13 mutants rapidly and reproducibly emerged in transfectants. Virus also acquired mutations in genes UL128, UL130, or UL131A, which inhibited virus growth specifically in fibroblast cells in wild-type form. We further report that RL13 encodes a highly glycosylated virion envelope protein and thus has the potential to modulate tropism. To overcome rapid emergence of mutations in genetically intact HCMV, we developed a system in which RL13 and UL131A were conditionally repressed during virus propagation. This technological advance now permits studies to be undertaken with a clonal, characterized HCMV strain containing the complete wild-type gene complement and promises to enhance the clinical relevance of fundamental research on HCMV.

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Coinfection of the immunocompromised but not the immunocompetent host by multiple human cytomegalovirus strains

Cited by 30 publications

References 17 publications

Frequent Coinfection of Cells Explains Functional In Vivo Complementation between Cytomegalovirus Variants in the Multiply Infected Host

Frequent Coinfection of Cells Explains Functional In Vivo Complementation between Cytomegalovirus Variants in the Multiply Infected Host

Genomes of the endothelial cell‐tropic variant and the parental Toledo strain of human cytomegalovirus are highly divergent

Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication

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