Human cytomegalovirus : development of resistance to antiviral drugs and mechanisms of NK-cell evasion
Author: Mousavi-Jazi, Mehrdad
Date: 2001-10-19
Location: Samuelssonsalen, Sheele-Laboratoriet, Tomtebodavägen 6
Time: 9.00
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
Human cytomegalovirus (HCMV), a member of the herpesviridae, is
ubiquitous and causes persistent infections mostly without any clinical
symptoms. However, HCMV infection is a major cause of morbidity and
mortality among immunocompromised patients, especially transplant
recipients and patients with AIDS. Antiviral agents currently licensed
for the treatment of HCMV infections include ganciclovir, foscarnet, and
cidofovir. Clinical management of HCMV infections in severely
immunocompromised patients often requires prolonged antiviral treatment,
which is associated with the risk of development of resistanct virus.
HCMV isolates resistant to antiviral agents have been selected in the
laboratory and have also been recovered from immunocompromised patients
treated with antiviral drugs. Studies performed in the last 5 years have
contributed significantly to the current understanding of the mechanisms
of resistance of HCMV to antiviral drugs.
We could identify isolates from AIDS patients, that had alterations within the viral phosphotransferase (pUL97) and/or DNA polymerase (pUL54) and which conferred drug resistance. However, we found no evidence that short term antiviral treatment of HCMV disease in renal transplant recipients induced resistance. By in vitro mutagenesis and induction of HCMV mutants in cell culture, it was determined that mutations in UL54 and UL97 genes induced reduced susceptibility to PFA and/or GCV. The mutated Towne strains had the same growth phenotype as the original HCMW Towne. Clinical HCMV isolates were shown to replicate either rapidly or slowly. Slow or fast replication was neither related to major immediate early gene exon 4, gB genotypes, nor to antiviral susceptibility.
The NK cells are of importance for the innate immune response to viral infections and may play a key role in the control of HCMV infections. In humans, low NK cell cytotoxicity is associated with increased sensitivity to herpesviruses infections, including CMV. The mechanism by which NK cells may recognize and eliminate virus-infected cells is still unclear. HCMV has evolved strategies to protect infected cells from lysis caused by NK cells, a feature that may have a role in the pathogenesis of HCMV disease. We found that the clinical isolates confer a strong NK resistance, whereas only marginal or variable effects in recognition were found when laboratory strains were used. The NK cell inhibition did not correlate with HLA class I expression and was independent of the leukocyte Ig-like receptor- I (LIR-1). The upregulation of HLA-E mediated by CMV pUL40 and IFN-gamma is one possible mechanism to avoid NK cell recognition of HCMV infected cells.
We could identify isolates from AIDS patients, that had alterations within the viral phosphotransferase (pUL97) and/or DNA polymerase (pUL54) and which conferred drug resistance. However, we found no evidence that short term antiviral treatment of HCMV disease in renal transplant recipients induced resistance. By in vitro mutagenesis and induction of HCMV mutants in cell culture, it was determined that mutations in UL54 and UL97 genes induced reduced susceptibility to PFA and/or GCV. The mutated Towne strains had the same growth phenotype as the original HCMW Towne. Clinical HCMV isolates were shown to replicate either rapidly or slowly. Slow or fast replication was neither related to major immediate early gene exon 4, gB genotypes, nor to antiviral susceptibility.
The NK cells are of importance for the innate immune response to viral infections and may play a key role in the control of HCMV infections. In humans, low NK cell cytotoxicity is associated with increased sensitivity to herpesviruses infections, including CMV. The mechanism by which NK cells may recognize and eliminate virus-infected cells is still unclear. HCMV has evolved strategies to protect infected cells from lysis caused by NK cells, a feature that may have a role in the pathogenesis of HCMV disease. We found that the clinical isolates confer a strong NK resistance, whereas only marginal or variable effects in recognition were found when laboratory strains were used. The NK cell inhibition did not correlate with HLA class I expression and was independent of the leukocyte Ig-like receptor- I (LIR-1). The upregulation of HLA-E mediated by CMV pUL40 and IFN-gamma is one possible mechanism to avoid NK cell recognition of HCMV infected cells.
List of papers:
I. Mousavi-Jazi M, Schloss L, Drew WL, Linde A, Miner RC, Harmenberg J, Wahren B, Brytting M (2001). "Variations in the cytomegalovirus DNA polymerase and phosphotransferase genes in relation to foscarnet and ganciclovir sensivity." J Clin Virol (In Print)
II. Mousavi-Jazi M, Hokeberg I, Schloss L, Zweygberg-Wirgart B, Grillner L, Linde A, Brytting M (2001). "Sequence analysis of UL54 and UL97 genes and evalution of antiviral susceptibility of HCMV isolates obtained from kidney allograft recipients before and after treatment." Transplant Infect Dis (Accepted)
III. Mousavi-Jazi M, Sundqvist VA, Linde A, Wahren B, Brytting M (2000). "Growth phenotypes of cytomegalovirus isolates do not correlate with glycoprotein B, major immediate early genotypes or antiviral sensitivity" J Med Virol 62(2): 117-26
Pubmed
IV. Mousavi-Jazi M, Schloss L, Wahren B, Brytting M (2001). "Évaluation of point mutations in the human cytomegalovirus DNA polymerase selected in vitro by foscarnet." (Submitted)
V. Cerboni C, Mousavi-Jazi M, Linde A, Soderstrom K, Brytting M, Wahren B, Karre K, Carbone E (2000). "Human cytomegalovirus strain-dependent changes in NK cell recognition of infected fibroblasts. " J Immunol 164(9): 4775-82
Pubmed
VI. Cerboni C, Mousavi-Jazi M, Wakiguti H, Carbone E, Karre K, Soderstrom K (2001). "Synergistic effect of IFN-gamma and the human cytomegalovirus protein UL40 in the HLA-E dependent protection from NK cell-mediated cytotoxicity." J Eur Immunol (Accepted)
I. Mousavi-Jazi M, Schloss L, Drew WL, Linde A, Miner RC, Harmenberg J, Wahren B, Brytting M (2001). "Variations in the cytomegalovirus DNA polymerase and phosphotransferase genes in relation to foscarnet and ganciclovir sensivity." J Clin Virol (In Print)
II. Mousavi-Jazi M, Hokeberg I, Schloss L, Zweygberg-Wirgart B, Grillner L, Linde A, Brytting M (2001). "Sequence analysis of UL54 and UL97 genes and evalution of antiviral susceptibility of HCMV isolates obtained from kidney allograft recipients before and after treatment." Transplant Infect Dis (Accepted)
III. Mousavi-Jazi M, Sundqvist VA, Linde A, Wahren B, Brytting M (2000). "Growth phenotypes of cytomegalovirus isolates do not correlate with glycoprotein B, major immediate early genotypes or antiviral sensitivity" J Med Virol 62(2): 117-26
Pubmed
IV. Mousavi-Jazi M, Schloss L, Wahren B, Brytting M (2001). "Évaluation of point mutations in the human cytomegalovirus DNA polymerase selected in vitro by foscarnet." (Submitted)
V. Cerboni C, Mousavi-Jazi M, Linde A, Soderstrom K, Brytting M, Wahren B, Karre K, Carbone E (2000). "Human cytomegalovirus strain-dependent changes in NK cell recognition of infected fibroblasts. " J Immunol 164(9): 4775-82
Pubmed
VI. Cerboni C, Mousavi-Jazi M, Wakiguti H, Carbone E, Karre K, Soderstrom K (2001). "Synergistic effect of IFN-gamma and the human cytomegalovirus protein UL40 in the HLA-E dependent protection from NK cell-mediated cytotoxicity." J Eur Immunol (Accepted)
Issue date: 2001-09-28
Publication year: 2001
ISBN: 91-7349-012-1
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