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Transplantation and Cellular Therapy Jun 2023Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and... (Review)
Review
Human herpesvirus 6 (HHV-6) reactivation is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with higher mortality and increased transplantation-related complications. We hypothesized that preemptive treatment with a short course of foscarnet at a lower cutpoint of plasma HHV-6 viral load would be effective in treating early HHV-6 reactivation, preventing complications and precluding hospitalization of these patients. We reviewed outcomes of adult patients (age ≥18 years) who received preemptive treatment with once-daily foscarnet 60 to 90 mg/kg for 7 days for HHV-6 reactivation after allo-HSCT at our institution between May 2020 and November 2022. Plasma HHV-6 viral load was monitored by quantitative PCR twice monthly in the first 100 days post-transplantation and twice weekly after reactivation until resolution. Eleven patients with a median age of 46 years (range, 23 to 73 years) were included in the analysis. HSCT was performed with a haploidentical donor in 10 patients and with an HLA-matched related donor in 1 patient. The most common diagnosis was acute leukemia (9 patients). Myeloablative and reduced-intensity conditioning regimens were used in 4 and 7 patients, respectively. Ten of the 11 patients received post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. The median follow-up was 440 days (range, 174 to 831 days), and the median time to HHV-6 reactivation was 22 days post-transplantation (range, 15 to 89 days). The median viral load at first reactivation was 3,100 copies/mL (range, 210 to 118,000 copies/mL), and the median peak viral load was 11,300 copies/mL (range, 600 to 983,000 copies/mL). All patients received a short course of foscarnet at either 90 mg/kg/day (n = 7) or 60 mg/kg/day (n = 4). In all patients, plasma HHV-6 DNA was undetectable at completion of 1 week of treatment. No HHV-6 encephalitis or pneumonitis occurred. All patients achieved neutrophil and platelet engraftment after a median of 16 days (range, 8 to 22 days) and 26 days (range, 14 to 168 days), respectively, with no secondary graft failure. No complications related to foscarnet administration were noted. One patient with very high HHV-6 viremia had recurrent reactivation and received a second course of foscarnet as an outpatient. A short course of once-daily foscarnet is effective in treating early HHV-6 reactivation post-transplantation and may reduce the incidence of HHV-6-related and treatment-related complications and preclude hospitalization in these patients.
Topics: Adult; Humans; Young Adult; Middle Aged; Aged; Adolescent; Foscarnet; Herpesvirus 6, Human; Hematopoietic Stem Cell Transplantation; Transplantation, Homologous; DNA, Viral
PubMed: 36878429
DOI: 10.1016/j.jtct.2023.02.022 -
American Journal of Therapeutics
Topics: Humans; Diabetes Insipidus, Nephrogenic; Foscarnet; Diabetes Insipidus; Diabetes Mellitus
PubMed: 32568860
DOI: 10.1097/MJT.0000000000001211 -
Journal of Virology Aug 2023The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi's...
The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus and the alpha-herpesviruses herpes simplex virus (HSV)-1 and HSV-2 have evolved an efficient mechanism to avoid APOBEC3 restriction by directly binding to APOBEC3B and facilitating its exclusion from the nuclear compartment. The only viral protein required for APOBEC3B relocalization is the large subunit of the ribonucleotide reductase (RNR). Here, we ask whether this APOBEC3B relocalization mechanism is conserved with the beta-herpesvirus human cytomegalovirus (HCMV). Although HCMV infection causes APOBEC3B relocalization from the nucleus to the cytoplasm in multiple cell types, the viral RNR (UL45) is not required. APOBEC3B relocalization occurs rapidly following infection suggesting the involvement of an immediate early or early (IE/E) viral protein. In support of this possibility, genetic (IE1 mutant) and pharmacologic (cycloheximide) strategies that prevent the expression of IE/E viral proteins also block APOBEC3B relocalization. In comparison, the treatment of infected cells with phosphonoacetic acid, which interferes with viral late protein expression, still permits A3B relocalization. These results combine to indicate that the beta-herpesvirus HCMV uses an RNR-independent, yet phenotypically similar, molecular mechanism to antagonize APOBEC3B. IMPORTANCE Human cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection.
Topics: Humans; Infant, Newborn; Cytidine Deaminase; Cytomegalovirus; DNA Replication; DNA, Viral; Epstein-Barr Virus Infections; Herpesviridae Infections; Herpesvirus 1, Human; Herpesvirus 4, Human; Immediate-Early Proteins; Minor Histocompatibility Antigens; Ribonucleotide Reductases; Viral Proteins; Virus Replication
PubMed: 37565748
DOI: 10.1128/jvi.00781-23 -
Transplantation Proceedings Mar 2018Resistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene). (Review)
Review
BACKGROUND
Resistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene).
METHODS
We describe our experience in management of R-CMV after renal transplant at our center (2012-2016).
RESULTS
We encountered 3 cases of R-CMV infection after renal transplant (all primary infections). All 3 patients received induction therapy with corticosteroids, tacrolimus, and mycophenolate mofetil. The first patient (basiliximab induction, preemptive CMV) developed CMV replication on day +53, which responded poorly both to standard-dose valganciclovir (vGCV) and high-dose ganciclovir (GCV) (creatinine clearance [CrCl] >70 mL/min; vGCV 900 mg twice daily for 50 days and GCV 7.5 mg/kg twice daily for 8 days). Hematologic toxicity occurred. The R-CMV test was positive and foscarnet (FOS) was initiated (90 mg/kg twice daily for 21 days). The second patient presented CMV infection (day +30, thymoglobulin induction, CMV prophylaxis), which was not controlled with the high dose (CrCl 23 mL/min; GCV 3.5 mg/kg twice daily and vGCV 900 mg twice daily), resulting in severe neutropenia. R-CMV was detected and FOS initiated (FOS 50 mg/kg twice daily for 7 days and 50 mg/kg every 2 days for 13 days). The third patient's infection occurred on day +22 (basiliximab induction, preemptive CMV). Standard-dose vGCV was uneffective (CrCl >70 mL/min, vGCV 900 mg twice daily) and it did not respond to the high dose (GCV 7.5 mg/kg twice daily and vGCV 2700 mg/d). Moderate hematologic toxicity occurred. R-CMV was diagnosed and FOS treatment begun (FOS 70 mg/kg per day for 2 weeks).
CONCLUSIONS
Resistant CMV infection may be severe due to viral infection and side effects of high-dose antiviral treatment. We presented 3 cases requiring the use of FOS in the absence of response or toxic effects from the usual treatment, with an optimal sustained response (temporary in case 2) and without serious side effects.
Topics: Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Antiviral Agents; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Multiple, Viral; Female; Foscarnet; Ganciclovir; Humans; Induction Chemotherapy; Kidney Transplantation; Male; Middle Aged; Mutation; Postoperative Complications; Recombinant Fusion Proteins; Tacrolimus; Valganciclovir; Virus Replication
PubMed: 29579856
DOI: 10.1016/j.transproceed.2017.09.058 -
Virus Research Apr 2017Vaccinia virus is the prototypic poxvirus. The 192 kilobase double-stranded DNA viral genome encodes most if not all of the viral replication machinery. The vaccinia... (Review)
Review
Vaccinia virus is the prototypic poxvirus. The 192 kilobase double-stranded DNA viral genome encodes most if not all of the viral replication machinery. The vaccinia virus DNA polymerase is encoded by the E9L gene. Sequence analysis indicates that E9 is a member of the B family of replicative polymerases. The enzyme has both polymerase and 3'-5' exonuclease activities, both of which are essential to support viral replication. Genetic analysis of E9 has identified residues and motifs whose alteration can confer temperature-sensitivity, drug resistance (phosphonoacetic acid, aphidicolin, cytosine arabinsode, cidofovir) or altered fidelity. The polymerase is involved both in DNA replication and in recombination. Although inherently distributive, E9 gains processivity by interacting in a 1:1 stoichiometry with a heterodimer of the A20 and D4 proteins. A20 binds to both E9 and D4 and serves as a bridge within the holoenzyme. The A20/D4 heterodimer has been purified and can confer processivity on purified E9. The interaction of A20 with D4 is mediated by the N'-terminus of A20. The D4 protein is an enzymatically active uracil DNA glycosylase. The DNA-scanning activity of D4 is proposed to keep the holoenzyme tethered to the DNA template but allow polymerase translocation. The crystal structure of D4, alone and in complex with A20 and/or DNA has been solved. Screens for low molecular weight compounds that interrupt the A20/D4 interface have yielded hits that disrupt processive DNA synthesis in vitro and/or inhibit plaque formation. The observation that an active DNA repair enzyme is an integral part of the holoenzyme suggests that DNA replication and repair may be coupled.
Topics: DNA, Viral; DNA-Directed DNA Polymerase; Protein Binding; Protein Multimerization; Recombination, Genetic; Uracil-DNA Glycosidase; Vaccinia virus; Viral Proteins; Virus Replication
PubMed: 28159613
DOI: 10.1016/j.virusres.2017.01.027 -
Antiviral Research Jul 2023Cytomegalovirus (CMV) is a significant human pathogen, especially for immunocompromised patients, often treated with one or more antiviral drugs. Although the prevalence...
Cytomegalovirus (CMV) is a significant human pathogen, especially for immunocompromised patients, often treated with one or more antiviral drugs. Although the prevalence of resistance is low, the impact of drug resistant CMV infections on patient outcomes is high and genotypic testing is recommended when resistance is suspected. To assess the prevalence of CMV drug resistance mutations among samples submitted for genotypic testing, 2750 patient sample results were analyzed. Testing was performed by sequencing for ganciclovir (GCV), cidofovir (CDV), foscarnet (FOS), maribavir (MBV) and/or letermovir (LMV) resistance conferring mutations. Of the 2750 patient samples, 826 (30.04%) had resistance to one or more anti-CMV drug. Resistance mutations were most common in UL97, with 27.64% and 9.96% of samples having GCV and MBV mutations, respectively. Resistance mutations in UL54 were less common, with 6.11%, 5.98% and 1.76% of samples having GCV, CDV and FOS mutations, respectively. For LMV, resistance mutations in UL56 were present in 7.17% of samples, with mutations at codon 325 representing 80.95% of the observed LMV resistance mutations. Resistance to two drugs was identified in 215 samples and to 3 or more drugs in 35 samples. While a high prevalence of CMV resistance mutations was identified, this must be taken in the context of healthcare providers submitting samples from patients with suspected resistant CMV strains. For these patients, rapid monitoring for resistance allows treatment modifications based on objective results rather than empiric drug selection, which is particularly relevant given the presence of mutations conferring resistance to more than one drug.
Topics: Humans; Cytomegalovirus; Prevalence; Transplant Recipients; DNA-Directed DNA Polymerase; Viral Proteins; Antiviral Agents; Ganciclovir; Foscarnet; Cidofovir; Drug Resistance, Viral; Mutation; Benzimidazoles
PubMed: 37150409
DOI: 10.1016/j.antiviral.2023.105623 -
Oral Diseases Apr 2024Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in... (Review)
Review
Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self-limiting, HSV-infections in immunocompromised patients are frequently more aggressive, persistent, and even life-threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.
Topics: Humans; Antiviral Agents; Drug Resistance, Viral; Acyclovir; Herpesvirus 1, Human; Immunocompromised Host; Stomatitis, Herpetic; Herpesvirus 2, Human; Cidofovir; Foscarnet
PubMed: 37279074
DOI: 10.1111/odi.14635 -
Drugs Jul 2018Cytomegalovirus (CMV) continues to be one of the most important pathogens that universally affect solid organ and allogeneic hematopoietic stem cell transplant... (Review)
Review
Cytomegalovirus (CMV) continues to be one of the most important pathogens that universally affect solid organ and allogeneic hematopoietic stem cell transplant recipients. Lack of effective CMV-specific immunity is the common factor that predisposes to the risk of CMV reactivation and clinical disease after transplantation. Antiviral drugs are the cornerstone for prevention and treatment of CMV infection and disease. Over the years, the CMV DNA polymerase inhibitor, ganciclovir (and valganciclovir), have served as the backbone for management, while foscarnet and cidofovir are reserved for the management of CMV infection that is refractory or resistant to ganciclovir treatment. In this review, we highlight the role of the newly approved drug, letermovir, a viral terminase inhibitor, for CMV prevention after allogeneic hematopoietic stem cell transplantation. Advances in immunologic monitoring may allow for an individualized approach to management of CMV after transplantation. Specifically, the potential role of CMV-specific T-cell measurements in guiding the need for the treatment of asymptomatic CMV infection and the duration of treatment of CMV disease is discussed. The role of adoptive immunotherapy, using ex vivo-generated CMV-specific T cells, is highlighted. This article provides a review of novel drugs, tests, and strategies in optimizing our current approaches to prevention and treatment of CMV in transplant recipients.
Topics: Acetates; Antiviral Agents; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Organ Transplantation; Quinazolines; Valganciclovir
PubMed: 29961185
DOI: 10.1007/s40265-018-0943-1 -
Current Hematologic Malignancy Reports Apr 2020CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often... (Review)
Review
PURPOSE OF REVIEW
CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection.
RECENT FINDINGS
Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.
Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Drug Resistance, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Immunotherapy; Immunotherapy, Adoptive; Molecular Targeted Therapy; Opportunistic Infections; Risk Factors; T-Lymphocytes; Treatment Outcome
PubMed: 31981100
DOI: 10.1007/s11899-020-00557-6 -
Journal of Virology Apr 2016Many viruses have the capacity to prevent a cell from being infected by a second virus, often termed superinfection exclusion. Alphaherpesviruses, including the human...
UNLABELLED
Many viruses have the capacity to prevent a cell from being infected by a second virus, often termed superinfection exclusion. Alphaherpesviruses, including the human pathogen herpes simplex virus 1 (HSV-1) and the animal herpesvirus pseudorabies virus (PRV), encode a membrane-bound glycoprotein, gD, that can interfere with subsequent virion entry. We sought to characterize the timing and mechanism of superinfection exclusion during HSV-1 and PRV infection. To this end, we utilized recombinant viruses expressing fluorescent protein (FP) markers of infection that allowed the visualization of viral infections by microscopy and flow cytometry as well as the differentiation of viral progeny. Our results demonstrated the majority of HSV-1- and PRV-infected cells establish superinfection exclusion by 2 h postinfection. The modification of viral infections by virion inactivation and phosphonoacetic acid, cycloheximide, and actinomycin D treatments indicated new protein synthesis is needed to establish superinfection exclusion. Primary infection with gene deletion PRV recombinants identified that new gD expression is not required to establish superinfection exclusion of a secondary viral inoculum. We also identified the timing of coinfection events during axon-to-cell spread, with most occurring within a 2-h window, suggesting a role for cellular superinfection exclusion during neuroinvasive spread of infection. In summary, we have characterized a gD-independent mechanism of superinfection exclusion established by two members of the alphaherpesvirus family and identified a potential role of exclusion during the pathogenic spread of infection.
IMPORTANCE
Superinfection exclusion is a widely observed phenomenon initiated by a primary viral infection to prevent further viruses from infecting the same cell. The capacity for alphaherpesviruses to infect the same cell impacts rates of interviral recombination and disease. Interviral recombination allows genome diversification, facilitating the development of resistance to antiviral therapeutics and evasion of vaccine-mediated immune responses. Our results demonstrate superinfection exclusion occurs early, through a gD-independent process, and is important in the directed spread of infection. Identifying when and where in an infected host viral genomes are more likely to coinfect the same cell and generate viral recombinants will enhance the development of effective antiviral therapies and interventions.
Topics: Animals; Cell Line; Cells, Cultured; Chlorocebus aethiops; Herpesvirus 1, Human; Herpesvirus 1, Suid; Rats; Reassortant Viruses; Superinfection; Vero Cells; Viral Envelope Proteins
PubMed: 26842480
DOI: 10.1128/JVI.00089-16