Case Report: Persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes

Oshima, Kiyohiro; Kanda, Yoshinobu; Kako, Shinichi; Asano‐Mori, Yuki; Watanabe, Takuro; Motokura, Toru; Shiraki, Kimíyasu; Kurokawa, Mineo

doi:10.1002/jmv.21277

Cited by 20 publications

(16 citation statements)

References 37 publications

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“…A patient with myelodysplastic syndrome developed persistent CMV antigenemia after hematopoietic stem cell transplantation, and CMV was isolated after treatment with ganciclovir and foscarnet. CMV was resistant to ganciclovir and foscarnet but sensitive to cidofovir and had mutations in UL97 (A594V) and UL54 (Q578H) (Oshima et al, 2008). This UL97 mutant was used as UL97 mutant A.…”

Section: Methodsmentioning

confidence: 99%

“…a Clones 14 and 46 were mizoribine-resistant clones isolated after culture for 3 months in the presence of 100 g/ml mizoribine. b UL97 mutants A and B were clinical isolates resistant to ganciclovir and had mutations in UL97 (A594V) and UL54 (Q578H) (Oshima et al, 2008) and UL97 (L595S), respectively.…”

Section: Susceptibility Of Ganciclovir-resistant Clinical Isolates Anmentioning

confidence: 99%

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Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Kuramoto

Daikoku²,

Yoshida³

et al. 2010

J Pharmacol Exp Ther

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Cytomegalovirus (CMV) infection is a prominent infection in transplant recipients. The immunosuppressive drug mizoribine was shown to have anti-CMV activity in vitro and was reported to have an anti-CMV effect in renal transplantation. This study characterized the anti-CMV activity of mizoribine in vitro and its synergistic activity with ganciclovir. Mizoribine suppressed replication and at the EC 50 for plaque inhibition of 12.0 g/ml.Mizoribine and ganciclovir exerted a strong synergism in anti-CMV activity. Mizoribine depletes guanosine nucleotides by inhibiting inosine monophosphate dehydrogenase and may increase the ratio of ganciclovir to guanosine in treated cells, resulting in a strong synergistic augmentation of the anti-CMV activity of ganciclovir. Two clinical isolates with UL97 mutations were less susceptible to mizoribine than the Towne strain but were equally susceptible in the presence of guanine. Two mizoribine-resistant strains were isolated after culture for 3 months with 100 g/ml mizoribine, but they were as sensitive to ganciclovir as the parent Towne strain. The anti-CMV activity of mizoribine was antagonized by 2Ј-deoxyguanosine. Mizoribine inhibited CMV replication directly, and the sequence of mizoribine-resistant mutants of UL97 and UL54 was identical to that of the parent Towne strain, indicating the different anti-CMV action from ganciclovir, foscarnet, and maribavir. Mizoribine as an immunosuppressive and anti-CMV drug in the clinical regimen was suggested to suppress replication of CMV in vivo and control CMV infection in transplant recipients in combination with ganciclovir.

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Section: Methodsmentioning

confidence: 99%

Section: Susceptibility Of Ganciclovir-resistant Clinical Isolates Anmentioning

confidence: 99%

Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Kuramoto

Daikoku²,

Yoshida³

et al. 2010

J Pharmacol Exp Ther

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“…The resultant supernatants were used as the cell-free virus stocks, and their virus titers ranged from 3.3 ϫ 10 3 to 2.3 ϫ 10 5 PFU/ml in this study. The Towne strain of cytomegalovirus (CMV) (18,28) and rhinovirus 13 (13) were propagated in HEL cells, and adenovirus 5 (19) was propagated in Hep2 cells. CMV, rhinovirus 13, and adenovirus 5 were prepared from the infected cells by three cycles of freezing and thawing.…”

Section: Cells and Virusesmentioning

confidence: 99%

Neutralizing Anti-gH Antibody of Varicella-Zoster Virus Modulates Distribution of gH and Induces Gene Regulation, Mimicking Latency

Shiraki

Daikoku

Takemoto

et al. 2011

J Virol

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The anti-glycoprotein H (gH) monoclonal antibody (anti-gH-MAb) that neutralizes varicella-zoster virus (VZV) inhibited cell-to-cell infection, resulting in a single infected cell without apoptosis or necrosis, and the number of infectious cells in cultures treated with anti-gH-MAb declined to undetectable levels in 7 to 10 days. Anti-gH-MAb modulated the wide cytoplasmic distribution of gH colocalized with glycoprotein E (gE) to the cytoplasmic compartment with endoplasmic reticulum (ER) and Golgi markers near the nucleus, while gE retained its cytoplasmic distribution. Thus, the disintegrated distribution of gH and gE caused the loss of cellular infectivity. Varicella-zoster virus (VZV) infection causes varicella, and then VZV becomes latent in the sensory ganglia. The reactivation of VZV caused zoster in every age group, especially in the elderly, at rates of 3 to 8 per 1,000 person-years in a study of 48,388 zoster patients (46). The major complication of zoster is chronic pain (postherpetic neuralgia); the pain is related to peripheral nerve injury and the activation of brain-derived neurotrophic factor by anti-immediate early (IE) 62 antibody (12). However, the mechanism of VZV latency is not clear. Studies of the latent human ganglia revealed the difference between gene regulation in VZV and herpes simplex virus (HSV). Transcripts from genes 21, 29, 62, 63, and 66 of VZV and the product from gene 63 have been identified in latently infected human ganglia (4-7, 16, 17, 20, 22, 51), in contrast to the presence of noncoding latency-associated transcripts of HSV (29, 40).The thymus leukemia antigen on the cell surface is lost due to anti-thymus leukemia antibody treatment, and this phenomenon is defined as the antigenic modulation of eukaryotic cells (25). Antigenic modulation also is observed in measles virusinfected cells. Antibodies to viral surface antigens modulate measles virus expression in the infected cells, and anti-hemagglutinin antibody reduces the expression of viral fusion protein, matrix protein, and phosphoprotein in measles virus-infected cells (9-11, 14, 26). The biological importance of antigenic modulation has been recognized in various cells by clearing the cell surface expression of the respective antigen with the relevant monoclonal antibody, including monoclonal antibody treatment for immunotherapy in B cells (30,31), red blood cells (52), a human thymic myoid cell line (48), B cells (2,3,45), and differentiating murine embryonic stem cells and embryo fibroblasts (39).VZV expresses the viral glycoproteins glycoprotein E (gE), glycoprotein B (gB), and glycoprotein H (gH) on the surface of infected cells. Anti-gH monoclonal antibody (anti-gH-MAb) neutralizes viral infectivity and inhibits cell-to-cell infection and plaque formation in vitro, while monoclonal antibodies to gE and gB and zoster convalescent-phase sera do not inhibit cell-to-cell infection. When infected cells were treated with anti-gH-MAb after cell-free virus infection, single-cell infection was observed without morphologi...

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“…However, alemtuzumab-based conditioning is associated with strong immune suppression and a delayed immune reconstitution after transplantation, which might lead to higher incidence of CMV reactivation. 29 Another possible disadvantage of alemtuzumab is that it might eliminate NK cells, which might be important for a GVM effect. 30 Koh et al reported that the lympholytic effect of alemtuzumab on NK cells was weaker than that on T cells and the use of alemtuzumab for ex vivo T cell depletion-alemtuzumab "in the bag"-resulted in the 99.8% and 94% depletion of CD4+ and CD8+ T cells, respectively, whereas 30% of NK cells were conserved in the graft.…”

Section: Alemtuzumab-based Conditioning Regimenmentioning

confidence: 99%

Haploidentical Stem Cell Transplantation

Nassar

2012

Hematology/Oncology and Stem Cell Therapy

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The feasibility of stem cell transplantation across the major histocompatibility barrier-as in haploidentical stem cell transplantation-has been proved for some time in several studies. The main limitations include a higher graft failure rate, delayed immune reconstitution after transplantation with high rates of life-threatening infections, a higher incidence of post-transplant lymphoproliferative disease, and severe acute and chronic graft-versus-host disease. In an attempt to reduce the transplant-related morbidity/mortality, several techniques had been evaluated involving conditioning regimen intensity, graft engineering, post-transplant cellular therapy and immunosuppression. This review will describe the current situation. It will also discuss initiatives and strategies to overcome the limitations associated with transplant across the MHC barrier.

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Case Report: Persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes

Cited by 20 publications

References 37 publications

Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Neutralizing Anti-gH Antibody of Varicella-Zoster Virus Modulates Distribution of gH and Induces Gene Regulation, Mimicking Latency

Haploidentical Stem Cell Transplantation

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