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1. What complications does CMV have in transplant patients?

1.1. Epidemiology/ taxonomy (genotyping)/drug resistance

1.1.1. hematopoietic stem cell transplant Frequent Occurrence of Cytomegalovirus Retinitis During Immune Reconstitution Warrants Regular Ophthalmic Screening in High-Risk Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients CMV retinitis during HSCT can lead to sight loss (patients should be given eye checks) (Atypical of other complications - high CD4, low CMV)

1.1.2. solid organ HCMV infection in renal transplant recipients: a retrospective cohort study. CMV disease correlates with graft rejection and increased complication events even when subclinical.

1.1.3. "pp65 antigenemia and real time polymerase chain reaction (PCR) based-study to determine the prevalence of human cytomegalovirus (HCMV) in kidney donors and recipients with follow-up studies". Despite donors being seronegative, recipients still develop CMV disease, suggesting CMV reactivates from recipients' latent pool. Characterization and immunological analysis of the rhesus cytomegalovirus homologue (Rh112) of the human cytomegalovirus UL83 lower matrix phosphoprotein (pp65). pp65-2 in Rh is a homolog of HCMV pp65 (pp65 is a target antigen of vaccines)

1.1.4. glycoprotein b Cytomegalovirus genotypes gB1 and gH1 are the most predominant genotypes among renal transplant recipients in Kuwait. gB1 gH1 is the most common strain of CMV in middle east. Showed no effect of genotype on clinical outcomes. Restriction enzyme analysis of the human cytomegalovirus genome in specimens collected from immunodeficient patients in Belém, State of Pará, Brazil. People can be coinfected with different glycoprotein B types. Especially when immunosuppressed. Human cytomegalovirus glycoprotein B genotypes in Chinese hematopoietic stem cell transplant recipient glycoprotein B1 genotype is the most common in Chinese HSCT patients, but glycoprotein B3 is associated with more reactivation/reinfection. Quantification of cytomegalovirus glycoprotein Bn DNA in hematopoietic stem cell transplant recipients by real-time PCR. PCR tests for CMV glycoprotein B DNA aids detection of CMV infection.

1.1.5. antiviral resistance A new mutation in the human cytomegalovirus UL97 gene may confer ganciclovir resistance in Chinese kidney transplant recipients. Mutations in UL97 gene confer CMV resistance to ganciclovir. Diversity of antiviral-resistant human cytomegalovirus in heart and lung transplant recipients. 43% of heart and lung transplant recipients with CMV had antviral resistant strains with mutations in UL54, F412S and D485N. antiviral resistance should be monitored in patients.

1.1.6. CMV causes disease? Dominance of variant A in human herpesvirus 6 viraemia after renal transplantation. HHV-6A (the other betaherpesvirus) is significantly associated with viremia and renal disease. Anti-HCMV IgG positivity rate among renal transplant recipients in Baghdad. Risk of CMV reactivation is associated with transplant recipients' anti-CMV igG seropositivity. [The dissemination of CMV in urine of different group from Guangxi and the relationship between CMV infection and renal disease]. CMV seropositivity is significantly associated with renal disease, and could be a causative agent.

1.2. Allograft screening / Cell tropism

1.2.1. Perivascular stromal cells as a potential reservoir of human cytomegalovirus. Lung- and Bone marrow- derived perivascular stromal cells are the most permissive reservoirs for CMV.

1.2.2. Detection of human cytomegalovirus in transbronchial biopsies from lung transplant recipients. Transbronchial biopsy detection is associated with CMV pneumonia, making it a useful clinical test in lung transplant recipients.

2. What are the current therapies?

2.1. Diagnostics/Prognosis

2.1.1. Prospective analysis of human cytomegalovirus DNAemia and specific CD8+ T cell responses in lung transplant recipients.

2.1.2. Determination of human cytomegalovirus pp65 antigenemia among renal transplant patients.

2.1.3. The lack of cytomegalovirus-specific cellular immune response may contribute to the onset of organ infection and disease in lung transplant recipients.

2.1.4. Differential outcome of neurological HCMV infection in two hematopoietic stem cell transplant recipients

2.1.5. Kinetics of human cytomegalovirus (HCMV) DNAemia in transplanted patients expressed in international units as determined with the Abbott RealTime CMV assay and an in-house assay.

2.1.6. Cytomegalovirus prophylaxis in solid organ transplantation.

2.1.7. Human cytomegalovirus-specific T-cell immune reconstitution in preemptively treated heart transplant recipients identifies subjects at critical risk for infection.

2.1.8. Simultaneous monitoring of cytomegalovirus-specific antibody and T-cell levels in seropositive heart transplant recipients.

2.1.9. Virologic and immunologic monitoring of cytomegalovirus to guide preemptive therapy in solid-organ transplantation.

2.1.10. Viral factors influencing the outcome of human cytomegalovirus infection in liver transplant recipients.

2.1.11. Individualised therapy Association of vitamin D receptor FokI and ApaI polymorphisms with human cytomegalovirus disease in the first three months following kidney transplantation. Impact of HLA-G 14-bp polymorphism on acute rejection and cytomegalovirus infection in kidney transplant recipients from northwestern China. HLA-G 14bp polymorphisms were deterministic of risk of both graft rejection and CMV infection demonstrating importance of genotypic risk assessments. Investigation of promoter variations in dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) (CD209) and their relevance for human cytomegalovirus reactivation and disease after allogeneic stem-cell transplantation. Reactivation risk is associated with particular polymorphisms in DC-SIGN promoter region after allogeneic stem cell transplant.

2.2. Experimental & standard treatments

2.2.1. passive immunity (igG)

2.2.2. Adoptive cell transfer Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ T Cells Are Both Required for Prevention of HCMV Disease in Seropositive Solid-Organ Transplant Recipients. Dendritic cell vaccination in an allogeneic stem cell recipient receiving a transplant from a human cytomegalovirus (HCMV)-seronegative donor: induction of a HCMV-specific T(helper) cell response. Human cytomegalovirus-specific T cell reconstitution in young patients receiving T cell-depleted, allogeneic hematopoietic stem cell transplantation. Adoptive immunotherapy of HCMV infection. Augmentation of virus-specific immunity after hematopoietic stem cell transplantation by adoptive T-cell therapy.

2.2.3. antiviral drugs/substances Inhibition of cytomegalovirus infection and photothermolysis of infected cells using bioconjugated gold nanoparticles. Rapamycin does not inhibit HCMV reactivation from dendritic cells in vitro. Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study. Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed? The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase.

2.2.4. immunogenic Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA-Transfected Dendritic Cells. Recent approaches and strategies in the generation of antihuman cytomegalovirus vaccines. The next generation recombinant human cytomegalovirus vaccine candidates-beyond gB. Vectored co-delivery of human cytomegalovirus gH and gL proteins elicits potent complement-independent neutralizing antibodies.

2.3. HCMV Protein LUNA Is Required for Viral Reactivation from Latently Infected Primary CD14+ Cells

2.3.1. Without LUNA protein upon initial latency, HCMV cannot reactivate from latent infection. (UL81-82ast, encoding the protein LUNA (Latency Unique Natural Antigen)

3. How does CMV evade immune detection?

3.1. Methods of investigation

3.1.1. Models HCMV infection of humanized mice after transplantation of G-CSF-mobilized peripheral blood stem cells from HCMV-seropositive donors. Differences between mouse and human cytomegalovirus interactions with their respective hosts at immediate early times of the replication cycle. Antibody responses to rhesus cytomegalovirus glycoprotein B in naturally infected rhesus macaques. RhCMV has similar evolution, protein chains and DNA sequences and share similar humoral response to glycoprotein B. beta-Herpesvirus (human cytomegalovirus and human herpesvirus 6) reactivation in at-risk lung transplant recipients and in human immunodeficiency virus-infected patients. HCMV and HHV6 may not have same reactivation components. HHV-6A, 6B, and 7: molecular basis of latency and reactivation.

3.2. Immune system responses

3.2.1. Systemic and local human cytomegalovirus-specific T-cell response in lung transplant recipients.

3.2.2. An evaluation of the role of NKG2C+ natural killer cells in protection from cytomegalovirus DNAemia early following allogeneic stem cell transplantation.

3.2.3. Association of human cytomegalovirus DNAaemia and specific granzyme B responses in lung transplant recipients.

3.2.4. Normalizing ELISPOT responses to T-cell counts: a novel approach for quantification of HCMV-specific CD4(+) and CD8(+) T-cell responses in kidney transplant recipients.

3.2.5. Deep sequencing of antiviral T-cell responses to HCMV and EBV in humans reveals a stable repertoire that is maintained for many years.

3.2.6. Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection.

3.2.7. Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature.

3.2.8. Impact of HCMV Infection on NK Cell Development and Function after HSCT.

3.2.9. Human cytomegalovirus specific CD8(+) T lymphocytes display interferon-gamma secretion impairment in kidney transplant recipients with pp65 antigenemia.

3.2.10. Cytomegalovirus infection after orthotopic liver transplantation is restricted by a pre-existing antiviral immune response of the recipient.

3.3. Viral effects on immune system / immunomodulatory complications

3.3.1. Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon.

3.3.2. Altered microRNA expression after infection with human cytomegalovirus leads to TIMP3 downregulation and increased shedding of metalloprotease substrates, including MICA.

3.3.3. B-cell-activating factor code and human cytomegalovirus infection in renal transplant recipients.

3.3.4. Cytomegalovirus-Responsive γδ T Cells: Novel Effector Cells in Antibody-Mediated Kidney Allograft Microcirculation Lesions. γδ T Cells

3.3.5. Cytomegalovirus-induced immunopathology and its clinical consequences.

3.3.6. Human cytomegalovirus infection in lung transplant recipients triggers a CXCL-10 response.

3.3.7. Cytomegalovirus impairs the induction of indoleamine 2,3-dioxygenase mediated antimicrobial and immunoregulatory effects in human fibroblasts.

3.3.8. Cytomegalovirus CC chemokine promotes immune cell migration.

3.3.9. Human cytomegalovirus latent infection of myeloid cells directs monocyte migration by up-regulating monocyte chemotactic protein-1.

3.3.10. Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer?

3.3.11. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells.

4. How does CMV reactivate in transplant patients?

4.1. HCMV reactivation

4.1.1. Terminal differentiation of myeloid progenitor reactivates CMV Reactivation of human cytomegalovirus in dendritic cells. CMV disease originates from recipients' latent resevoir and not donors'. Circulating dendritic cells isolated from healthy seropositive donors are sites of human cytomegalovirus reactivation in vivo. A hypothesis is that inflammation increases reactivation through the differentiation of myeloid into Dentritic cells, which is an event associated with reactivation. The intimate relationship between human cytomegalovirus and the dendritic cell lineage. it is now established that terminal differentiation of myeloid progenitors leads to reactivation. DC is site of lytic infection and reactivation. Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. humanised mice models show that granulocyte-colony stimulating factor mobilized stem cells from donors with CMV increases risk of CMV transmission.

4.1.2. immune cells activating Preliminary exploration of HLA-A 1101-restricted human cytomegalovirus glycoprotein B-specific CD8⁺ T cells in allogeneic stem-cell transplant recipients. Cross-reactive anti-viral T cells increase prior to an episode of viral reactivation post human lung transplantation CMV reactivation is associate with cross-reaction between CMV-specific T cells and donor Human Leukocyte antigens (HLA); thereby reducing the availability of CMV-specific T cells. IL6 <> mitogen and stress activated protein kinase Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells. Mitogen and stress activated kinases act co-operatively with CREB during the induction of human cytomegalovirus immediate-early gene expression from latency.

4.1.3. viral gene switches Aspects of human cytomegalovirus latency and reactivation. Cellular transcription factors and histone proteins have an impact on CMV latency and reactivation. CMV genomes are also active during latency. Antagonistic determinants controlling replicative and latent states of human cytomegalovirus infection. UL135 and UL138 are promoter and suppressor regions for reactivation, acting as molecular switches. (ULb' region) How virus controls latent state.

4.1.4. suppression by immune cells CMV induces rapid NK cell maturation in HSCT recipients. elevated NK cells with upregulated CD94/NKG2C receptor control CMV infection Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ T Cells Are Both Required for Prevention of HCMV Disease in Seropositive Solid-Organ Transplant Recipients. Elevated granzyme M-expressing lymphocytes during cytomegalovirus latency and reactivation after allogeneic stem cell transplantation. higher ratios of granzyme M-expressing lymphocytes seem to be associated with latency in comparison to reactivation. This could be used in adoptive immune therapy