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Chiara Fornara
Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy

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human cytomegalovirus
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Review
Published: 16 August 2021 in Microorganisms
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Congenital cytomegalovirus infection (cCMV) may affect about 1% of all newborns all over the world as a result of either a primary or recurrent human cytomegalovirus (HCMV) infection. While about 90% of infants affected by cCMV are asymptomatic at birth, the remaining 10% are symptomatic often with neurodevelopmental impairment and sensorineural hearing loss. In view of identifying the best approach to vaccine prevention of cCMV, this review will examine the most important steps made in the study of the immune response to, and diagnosis of, HCMV infection. The maternal immune response and immune correlates of protection are being partially identified with a partial contribution given by our laboratory. The diagnosis of primary infection is often difficult to achieve in the first three months of pregnancy, which is the time primarily involved in virus transmission to the fetus in association with the most severe symptoms and sequelae. Prevention of cCMV is anticipated by prevention of primary infection in early pregnancy by means of different measures, such as (i) behavioral-educational measures, (ii) immunoglobulin administration, (iii) antiviral treatment with valaciclovir. However, the most promising approach to cCMV prevention appears to be the development of a non-living vaccine, including at least three viral antigens: gB, pentamer complex gHgLpUL128L, and pp65, which have been shown to be able to stimulate both the humoral and the cellular arms of the maternal immune response. Primary HCMV infection may be managed in pregnancy by counseling of the couples involved by a team of specialists that includes virologists, obstetricians, infectivologists and neonatologists.

ACS Style

Giuseppe Gerna; Chiara Fornara; Milena Furione; Daniele Lilleri. Congenital Human Cytomegalovirus Infection: A Narrative Review of Maternal Immune Response and Diagnosis in View of the Development of a Vaccine and Prevention of Primary and Non-Primary Infections in Pregnancy. Microorganisms 2021, 9, 1749 .

AMA Style

Giuseppe Gerna, Chiara Fornara, Milena Furione, Daniele Lilleri. Congenital Human Cytomegalovirus Infection: A Narrative Review of Maternal Immune Response and Diagnosis in View of the Development of a Vaccine and Prevention of Primary and Non-Primary Infections in Pregnancy. Microorganisms. 2021; 9 (8):1749.

Chicago/Turabian Style

Giuseppe Gerna; Chiara Fornara; Milena Furione; Daniele Lilleri. 2021. "Congenital Human Cytomegalovirus Infection: A Narrative Review of Maternal Immune Response and Diagnosis in View of the Development of a Vaccine and Prevention of Primary and Non-Primary Infections in Pregnancy." Microorganisms 9, no. 8: 1749.

Journal article
Published: 03 March 2021 in Viruses
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Background: Strain-specific antibodies to human cytomegalovirus (HCMV) glycoproteins B and H (gB and gH) have been proposed as a potential diagnostic tool for identifying reinfection. We investigated genotype-specific IgG antibody responses in parallel with defining the gB and gH genotypes of the infecting viral strains. Methods: Subjects with primary (n = 20) or non-primary (n = 25) HCMV infection were studied. The seven gB (gB1-7) and two gH (gH1-2) genotypes were determined by real-time PCR and whole viral genome sequencing, and genotype-specific IgG antibodies were measured by a peptide-based enzyme-linked immunosorbent assay (ELISA). Results: Among subjects with primary infection, 73% (n = 8) infected by gB1-HCMV and 63% (n = 5) infected by gB2/3-HCMV had genotype-specific IgG antibodies to gB (gB2 and gB3 are similar in the region tested). Peptides from the rarer gB4-gB7 genotypes had nonspecific antibody responses. All subjects infected by gH1-HCMV and 86% (n = 6) infected by gH2-HCMV developed genotype-specific responses. Among women with non-primary infection, gB and gH genotype-specific IgG antibodies were detected in 40% (n = 10) and 80% (n = 20) of subjects, respectively. Conclusions: Peptide-based ELISA is capable of detecting primary genotype-specific IgG responses to HCMV gB and gH, and could be adopted for identifying reinfections. However, about half of the subjects did not have genotype-specific IgG antibodies to gB.

ACS Style

Federica Zavaglio; Loretta Fiorina; Nicolás Suárez; Chiara Fornara; Marica De Cicco; Daniela Cirasola; Andrew Davison; Giuseppe Gerna; Daniele Lilleri. Detection of Genotype-Specific Antibody Responses to Glycoproteins B and H in Primary and Non-Primary Human Cytomegalovirus Infections by Peptide-Based ELISA. Viruses 2021, 13, 399 .

AMA Style

Federica Zavaglio, Loretta Fiorina, Nicolás Suárez, Chiara Fornara, Marica De Cicco, Daniela Cirasola, Andrew Davison, Giuseppe Gerna, Daniele Lilleri. Detection of Genotype-Specific Antibody Responses to Glycoproteins B and H in Primary and Non-Primary Human Cytomegalovirus Infections by Peptide-Based ELISA. Viruses. 2021; 13 (3):399.

Chicago/Turabian Style

Federica Zavaglio; Loretta Fiorina; Nicolás Suárez; Chiara Fornara; Marica De Cicco; Daniela Cirasola; Andrew Davison; Giuseppe Gerna; Daniele Lilleri. 2021. "Detection of Genotype-Specific Antibody Responses to Glycoproteins B and H in Primary and Non-Primary Human Cytomegalovirus Infections by Peptide-Based ELISA." Viruses 13, no. 3: 399.

Journal article
Published: 26 February 2021 in Diagnostics
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Primary infection occurs when seronegative women are infected by human cytomegalovirus (HCMV). Diagnosis of primary infection is based on the following: antibody seroconversion, presence of IgM and low IgG avidity index (AI), and presence of DNAemia. The kinetics of HCMV-specific IgM antibody and maturation of AI might be very rapid or long-lasting during primary infection, which makes serological diagnosis insidious. The aims of this study were as follows: (i) to report atypical kinetics of HCMV-specific IgM antibody and AI early after onset of primary HCMV infection in a population of pregnant women, and (ii) to assess the frequency of such results. Altogether, 1309 sequential serum samples collected from 465 pregnant women with primary HCMV infection were included in the study. As a general rule, using the LIAISON®CMVIgMII and LIAISON®CMVIgGAvidityII assays, virus-specific IgM antibody levels decreased, while IgG AI increased over time during the first three months after infection onset. However, early clearance of IgM antibody and/or early IgG AI maturation occurred in 46/426 (10.7%) women. In more details, 20/426 (4.7%) and 26/418 (6.2%) women had undetectable IgM antibody or high IgG AI, respectively, when tested within 1–3 months after well-defined infection onset. Twenty sera from as many women with high IgG AI by the LIAISON assay were further tested for IgG AI by VIDAS®CMVIgGAvidityII and Mikrogen recomLineCMVIgG Avidity assays. Comparable results were obtained with VIDAS, whereas 14/20 sera gave low AI with the Mikrogen assay. In conclusion, about 11% of pregnant women undergoing a primary HCMV infection showed misleading serological results. Additional and appropriate testing might help in reducing the risk of missing HCMV primary infection in pregnancy. Furthermore, preconceptional testing should be strongly recommended.

ACS Style

Antonella Sarasini; Alessia Arossa; Maurizio Zavattoni; Chiara Fornara; Daniele Lilleri; Arsenio Spinillo; Fausto Baldanti; Milena Furione. Pitfalls in the Serological Diagnosis of Primary Human Cytomegalovirus Infection in Pregnancy Due to Different Kinetics of IgM Clearance and IgG Avidity Index Maturation. Diagnostics 2021, 11, 396 .

AMA Style

Antonella Sarasini, Alessia Arossa, Maurizio Zavattoni, Chiara Fornara, Daniele Lilleri, Arsenio Spinillo, Fausto Baldanti, Milena Furione. Pitfalls in the Serological Diagnosis of Primary Human Cytomegalovirus Infection in Pregnancy Due to Different Kinetics of IgM Clearance and IgG Avidity Index Maturation. Diagnostics. 2021; 11 (3):396.

Chicago/Turabian Style

Antonella Sarasini; Alessia Arossa; Maurizio Zavattoni; Chiara Fornara; Daniele Lilleri; Arsenio Spinillo; Fausto Baldanti; Milena Furione. 2021. "Pitfalls in the Serological Diagnosis of Primary Human Cytomegalovirus Infection in Pregnancy Due to Different Kinetics of IgM Clearance and IgG Avidity Index Maturation." Diagnostics 11, no. 3: 396.

Letter to the editor
Published: 29 August 2020 in European Journal of Immunology
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This article is protected by copyright. All rights reserved

ACS Style

Chiara Fornara; Milena Furione; Federica Zavaglio; Alessia Arossa; Arsenio Spinillo; Giuseppe Gerna; Daniele Lilleri. Slow cytomegalovirus‐specific CD4 + and CD8 + T‐cell differentiation: 10‐year follow‐up of primary infection in a small number of immunocompetent hosts. European Journal of Immunology 2020, 51, 253 -256.

AMA Style

Chiara Fornara, Milena Furione, Federica Zavaglio, Alessia Arossa, Arsenio Spinillo, Giuseppe Gerna, Daniele Lilleri. Slow cytomegalovirus‐specific CD4 + and CD8 + T‐cell differentiation: 10‐year follow‐up of primary infection in a small number of immunocompetent hosts. European Journal of Immunology. 2020; 51 (1):253-256.

Chicago/Turabian Style

Chiara Fornara; Milena Furione; Federica Zavaglio; Alessia Arossa; Arsenio Spinillo; Giuseppe Gerna; Daniele Lilleri. 2020. "Slow cytomegalovirus‐specific CD4 + and CD8 + T‐cell differentiation: 10‐year follow‐up of primary infection in a small number of immunocompetent hosts." European Journal of Immunology 51, no. 1: 253-256.

Case report
Published: 30 July 2020 in Diagnostics
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Human cytomegalovirus (HCMV) is the leading infectious agent causing congenital disabilities. The risk of HCMV transmission to the fetus in pregnant women receiving immunosuppressive agents is unknown. We describe two cases of pregnant women with evidence of pre-conception HCMV protective immunity receiving azathioprine for ulcerative colitis or systemic lupus erythematosus. Both women reactivated the HCMV and transmitted the infection to the fetuses. One newborn showed unilateral hearing deficits and brain abnormalities while the other was asymptomatic. The mother of the symptomatic newborn had low levels of total and HCMV-specific blood CD4+ T cells. Women receiving immunosuppressive agents deserve information about the risk of HCMV congenital infection and should be monitored for HCMV infection during pregnancy. Their newborns should be screened for HCMV congenital infection.

ACS Style

Paolo Ivo Cavoretto; Chiara Fornara; Cristina Baldoli; Alessia Arossa; Milena Furione; Massimo Candiani; Patrizia Rovere Querini; Graziano Barera; Antonella Poloniato; Gerarda Gaeta; Arsenio Spinillo; Daniele Lilleri. Prenatal Management of Congenital Human Cytomegalovirus Infection in Seropositive Pregnant Patients Treated with Azathioprine. Diagnostics 2020, 10, 542 .

AMA Style

Paolo Ivo Cavoretto, Chiara Fornara, Cristina Baldoli, Alessia Arossa, Milena Furione, Massimo Candiani, Patrizia Rovere Querini, Graziano Barera, Antonella Poloniato, Gerarda Gaeta, Arsenio Spinillo, Daniele Lilleri. Prenatal Management of Congenital Human Cytomegalovirus Infection in Seropositive Pregnant Patients Treated with Azathioprine. Diagnostics. 2020; 10 (8):542.

Chicago/Turabian Style

Paolo Ivo Cavoretto; Chiara Fornara; Cristina Baldoli; Alessia Arossa; Milena Furione; Massimo Candiani; Patrizia Rovere Querini; Graziano Barera; Antonella Poloniato; Gerarda Gaeta; Arsenio Spinillo; Daniele Lilleri. 2020. "Prenatal Management of Congenital Human Cytomegalovirus Infection in Seropositive Pregnant Patients Treated with Azathioprine." Diagnostics 10, no. 8: 542.

Journal article
Published: 13 September 2019 in Journal of Clinical Virology
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IgM and IgG avidity are not always reliable for diagnosis of primary HCMV infections. Anti-p52 IgM and anti-gB IgG provide additional tools in dating HCMV infections. Combination of different assays improves diagnosis and dating of HCMV infections.

ACS Style

Paola Zelini; Chiara Fornara; Milena Furione; Antonella Sarasini; Julia Klemens; Alessia Arossa; Arsenio Spinillo; Giuseppe Gerna; Daniele Lilleri. Determination of anti-p52 IgM and anti-gB IgG by ELISA as a novel diagnostic tool for detection of early and late phase of primary human cytomegalovirus infections during pregnancy. Journal of Clinical Virology 2019, 120, 38 -43.

AMA Style

Paola Zelini, Chiara Fornara, Milena Furione, Antonella Sarasini, Julia Klemens, Alessia Arossa, Arsenio Spinillo, Giuseppe Gerna, Daniele Lilleri. Determination of anti-p52 IgM and anti-gB IgG by ELISA as a novel diagnostic tool for detection of early and late phase of primary human cytomegalovirus infections during pregnancy. Journal of Clinical Virology. 2019; 120 ():38-43.

Chicago/Turabian Style

Paola Zelini; Chiara Fornara; Milena Furione; Antonella Sarasini; Julia Klemens; Alessia Arossa; Arsenio Spinillo; Giuseppe Gerna; Daniele Lilleri. 2019. "Determination of anti-p52 IgM and anti-gB IgG by ELISA as a novel diagnostic tool for detection of early and late phase of primary human cytomegalovirus infections during pregnancy." Journal of Clinical Virology 120, no. : 38-43.

Research article
Published: 10 July 2018 in Journal of Medical Virology
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Immune correlates of protection against human cytomegalovirus (HCMV) infection are still debated. This study aimed to investigate which arm of the immune response plays a major role in protection against HCMV infection in kidney (KTR, n=40) and heart transplant recipients (HTR, n= 12). Overall, patients were divided into two groups: one including 37 patients with low viral load (LVL), and the other including 15 patients with high viral load (HVL). All LVL patients resolved the infection spontaneously, whereas HVL patients were all treated with one or more courses of antivirals. In HVL patients, viral DNAemia, which was more than 100 times higher than LVL, appeared and peaked at significantly earlier times, but disappeared much later than in LVL patients. During a 1‐year follow‐up, all LVL patients had levels of HCMV‐specific CD4+ (and CD8+) T‐cells significantly higher than HVL patients. On the contrary, titers of neutralizing antibodies, and ELISA‐IgG antibody to gB, gHgLgO and pentamer gHgLpUL128L were overlapping in the two patient groups. In conclusion, while a valid HCMV‐specific T‐cell response was detected in more than 90% of LVL patients, >90% of HVL patients lacked an adequate T‐cell response. Antibody responses did not appear to be associated directly or indirectly with protection. This article is protected by copyright. All rights reserved.

ACS Style

Daniele Lilleri; Paola Zelini; Chiara Fornara; Federica Zavaglio; Teresa Rampino; Laurent Perez; Elisa Gabanti; Giuseppe Gerna. Human cytomegalovirus (HCMV)-specific T cell but not neutralizing or IgG binding antibody responses to glycoprotein complexes gB, gHgLgO, and pUL128L correlate with protection against high HCMV viral load reactivation in solid-organ transplant recipients. Journal of Medical Virology 2018, 90, 1620 -1628.

AMA Style

Daniele Lilleri, Paola Zelini, Chiara Fornara, Federica Zavaglio, Teresa Rampino, Laurent Perez, Elisa Gabanti, Giuseppe Gerna. Human cytomegalovirus (HCMV)-specific T cell but not neutralizing or IgG binding antibody responses to glycoprotein complexes gB, gHgLgO, and pUL128L correlate with protection against high HCMV viral load reactivation in solid-organ transplant recipients. Journal of Medical Virology. 2018; 90 (10):1620-1628.

Chicago/Turabian Style

Daniele Lilleri; Paola Zelini; Chiara Fornara; Federica Zavaglio; Teresa Rampino; Laurent Perez; Elisa Gabanti; Giuseppe Gerna. 2018. "Human cytomegalovirus (HCMV)-specific T cell but not neutralizing or IgG binding antibody responses to glycoprotein complexes gB, gHgLgO, and pUL128L correlate with protection against high HCMV viral load reactivation in solid-organ transplant recipients." Journal of Medical Virology 90, no. 10: 1620-1628.

Journal article
Published: 20 April 2018 in Journal of Clinical Virology
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An incorrect definition of immune status to human cytomegalovirus (HCMV) can lead to incorrect management of pregnant women. Aims of the study were: i) to describe 10 cases of unconfirmed HCMV IgG-seroconversion in pregnancy; ii) to develop a panel of confirmatory tests to define HCMV serostatus; iii) to investigate the frequency of false IgG-positive results in pregnant women screened with the LIAISON®CMVIgGII automated assay. Blood samples from 10 pregnant women referred for HCMV IgG-seroconversion were examined to confirm/exclude a primary infection. In addition, samples were tested for HCMV IgG by immunoblotting, neutralization assay, and ELISA against gB, gH/gL/pUL128L and gH/gL/gO recombinant glycoproteins. LIAISON®CMVIgGII results obtained on 1,158 pregnant women were reviewed and samples with low IgG titers were further investigated. A primary infection was excluded in the 10 women referred for HCMV IgG seroconversion. None of them was confirmed to be IgG-seropositive. Of the 1,158 women prenatally screened by LIAISON®CMVIgGII, 678 (59%) were IgG-positive and, of these, 40 (5.9%) showed low levels of IgG (14–50 U/mL). Thirty-three women with low IgG-positivity were further tested by confirmatory tests and 11 (33.3%) were found to be non reactive to HCMV. At least 1.6% (11/678) women who tested positive with LIAISON®CMVIgGII were found to be seronegative when tested with confirmatory tests. These women should be informed to reduce the risk of a primary HCMV infection. Furthermore, should a congenital infection occur in any of these women, a maternal non-primary infection could be erroneously diagnosed.

ACS Style

Milena Furione; Antonella Sarasini; Alessia Arossa; Chiara Fornara; Daniele Lilleri; Laurent Perez; Maurizio Parea; Maurizio Zavattoni; Arsenio Spinillo; Piero Marone; Fausto Baldanti; Fornara Chiara. False human cytomegalovirus IgG-positivity at prenatal screening. Journal of Clinical Virology 2018, 104, 34 -38.

AMA Style

Milena Furione, Antonella Sarasini, Alessia Arossa, Chiara Fornara, Daniele Lilleri, Laurent Perez, Maurizio Parea, Maurizio Zavattoni, Arsenio Spinillo, Piero Marone, Fausto Baldanti, Fornara Chiara. False human cytomegalovirus IgG-positivity at prenatal screening. Journal of Clinical Virology. 2018; 104 ():34-38.

Chicago/Turabian Style

Milena Furione; Antonella Sarasini; Alessia Arossa; Chiara Fornara; Daniele Lilleri; Laurent Perez; Maurizio Parea; Maurizio Zavattoni; Arsenio Spinillo; Piero Marone; Fausto Baldanti; Fornara Chiara. 2018. "False human cytomegalovirus IgG-positivity at prenatal screening." Journal of Clinical Virology 104, no. : 34-38.

Journal article
Published: 29 November 2017 in British Journal of Dermatology
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ACS Style

L. Fornara; R. Cananzi; D. Lilleri; M. Furione; V. Brazzelli. Incidence of human cytomegalovirus infection and T-cell response in patients with psoriasis before and during antitumour necrosis factor-α therapy. British Journal of Dermatology 2017, 177, e323 -e324.

AMA Style

L. Fornara, R. Cananzi, D. Lilleri, M. Furione, V. Brazzelli. Incidence of human cytomegalovirus infection and T-cell response in patients with psoriasis before and during antitumour necrosis factor-α therapy. British Journal of Dermatology. 2017; 177 (6):e323-e324.

Chicago/Turabian Style

L. Fornara; R. Cananzi; D. Lilleri; M. Furione; V. Brazzelli. 2017. "Incidence of human cytomegalovirus infection and T-cell response in patients with psoriasis before and during antitumour necrosis factor-α therapy." British Journal of Dermatology 177, no. 6: e323-e324.

Research article
Published: 07 November 2017 in PLoS ONE
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Congenital human cytomegalovirus (HCMV) infection is the major cause of birth defects and a precise definition of the HCMV-specific T-cell response in primary infection may help define reliable correlates of immune protection during pregnancy. In this study, a high throughput method was used to define the frequency of CD4+ and CD8+ T cells specific for four HCMV proteins in the naïve compartment of seronegative subjects and the effector/memory compartments of subjects with primary/remote HCMV infection. The naïve repertoire displayed comparable frequencies of T cells that were reactive with HCMV structural (pp65, gB and the pentamer gHgLpUL128L) and non-structural (IE-1) proteins. Whereas, following natural infection, the majority of effector/memory CD4+ and CD8+ T cells recognized either gB or IE-1, respectively, and pp65. The pattern of T cell reactivity was comparable at early and late stages of infection and in pregnant women with primary HCMV infection transmitting or not transmitting the virus to the fetus. At an early stage of primary infection, about 50% of HCMV-reactive CD4+ T cells were long-term IL-7Rpos memory cells, while 6–12 months later, the frequency of these cells increased to 70%, approaching 100% in remote infections. In contrast, only 10–20% of HCMV-specific CD8+ T cells were long-term memory cells up to 12 months after infection onset, thereafter increasing to 70% in remote infections. Interestingly, a significantly higher frequency of HCMV-specific CD4+ T cells with a long-term IL-7Rpos memory phenotype was observed in non-transmitting compared to transmitting women. These findings indicate that immunodominance in HCMV infection is not predetermined in the naïve compartment, but is the result of virus-host interactions and suggest that prompt control of HCMV infection in pregnancy is associated with the rapid development of long-term IL-7Rpos memory HCMV-specific CD4+ T cells and a low risk of virus transmission to the fetus.

ACS Style

Federico Mele; Chiara Fornara; David Jarrossay; Milena Furione; Alessia Arossa; Arsenio Spinillo; Antonio Lanzavecchia; Giuseppe Gerna; Federica Sallusto; Daniele Lilleri. Phenotype and specificity of T cells in primary human cytomegalovirus infection during pregnancy: IL-7Rpos long-term memory phenotype is associated with protection from vertical transmission. PLoS ONE 2017, 12, e0187731 .

AMA Style

Federico Mele, Chiara Fornara, David Jarrossay, Milena Furione, Alessia Arossa, Arsenio Spinillo, Antonio Lanzavecchia, Giuseppe Gerna, Federica Sallusto, Daniele Lilleri. Phenotype and specificity of T cells in primary human cytomegalovirus infection during pregnancy: IL-7Rpos long-term memory phenotype is associated with protection from vertical transmission. PLoS ONE. 2017; 12 (11):e0187731.

Chicago/Turabian Style

Federico Mele; Chiara Fornara; David Jarrossay; Milena Furione; Alessia Arossa; Arsenio Spinillo; Antonio Lanzavecchia; Giuseppe Gerna; Federica Sallusto; Daniele Lilleri. 2017. "Phenotype and specificity of T cells in primary human cytomegalovirus infection during pregnancy: IL-7Rpos long-term memory phenotype is associated with protection from vertical transmission." PLoS ONE 12, no. 11: e0187731.

Journal article
Published: 20 July 2017 in Clinical Infectious Diseases
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BackgroundPrimary human cytomegalovirus (HCMV) infection during pregnancy is the major cause of congenital viral sequelae. The HCMV-specific T-cell response may have a role in the prevention of virus transmission to the fetus.MethodsHCMV-specific memory T cells were investigated in the second month after primary infection onset in 44 pregnant women (15 transmitting the infection to the fetus) and 8 pregnant women with remote infection. Peripheral blood mononuclear cells were stimulated for 12 days with peptide pools of HCMV proteins IE-1, IE-2, and pp65, and subsequently restimulated for 24 hours with the same peptide pools in a cultured enzyme-linked immunospot (ELISPOT) assay.ResultsIn pregnant women with primary infection, the cultured ELISPOT assay detected a higher T-cell response to pp65 than to IE-1 or IE-2, whereas in remote infection pp65-, IE-1–, and IE-2–specific T cells were detected at comparable levels. During primary infection, the cultured ELISPOT response was mainly mediated by CD4+ T cells, and was lower than in remote infection. Strikingly, the cultured ELISPOT response to pp65 (but not to IE-1 or IE-2) was significantly higher in nontransmitting mothers. To detect other factors potentially associated with nontransmission, different serological parameters were analyzed. Only immunoglobulin G avidity index was higher in nontransmitting mothers, who showed also a lower DNAemia level. These 2 parameters remained associated with congenital infection in multivariate analysis.ConclusionsDetermination of HCMV-specific T cells by cultured ELISPOT, in pregnant women with primary HCMV infection, in association with avidity index and DNAemia may help to assess the risk of HCMV fetal transmission.

ACS Style

Chiara Fornara; Irene Cassaniti; Maurizio Zavattoni; Milena Furione; Kodjo Messan Guy Adzasehoun; Annalisa De Silvestri; Giuditta Comolli; Fausto Baldanti. Human Cytomegalovirus–Specific Memory CD4+ T-Cell Response and Its Correlation With Virus Transmission to the Fetus in Pregnant Women With Primary Infection. Clinical Infectious Diseases 2017, 65, 1659 -1665.

AMA Style

Chiara Fornara, Irene Cassaniti, Maurizio Zavattoni, Milena Furione, Kodjo Messan Guy Adzasehoun, Annalisa De Silvestri, Giuditta Comolli, Fausto Baldanti. Human Cytomegalovirus–Specific Memory CD4+ T-Cell Response and Its Correlation With Virus Transmission to the Fetus in Pregnant Women With Primary Infection. Clinical Infectious Diseases. 2017; 65 (10):1659-1665.

Chicago/Turabian Style

Chiara Fornara; Irene Cassaniti; Maurizio Zavattoni; Milena Furione; Kodjo Messan Guy Adzasehoun; Annalisa De Silvestri; Giuditta Comolli; Fausto Baldanti. 2017. "Human Cytomegalovirus–Specific Memory CD4+ T-Cell Response and Its Correlation With Virus Transmission to the Fetus in Pregnant Women With Primary Infection." Clinical Infectious Diseases 65, no. 10: 1659-1665.

Comparative study
Published: 01 August 2016 in Journal of General Virology
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Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (n=40) and immunocompromised transplanted patients (n=20) revealed that the median peak antibody titer neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: i) HCMV DNAemia; ii) HCMV neutralizing antibodies; iii) ELISA IgG antibody titer to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; iv) HCMV-specific (IFN-γ+) CD4+ and CD8+ T-cells. Circulating CXCR5+ CD4+ (memory T follicular helper -TFH- cells) were identified as activated TFH (ICOS+PD-1++CCR7lo) and quiescent cells. In the early stages of primary infection, activated TFH cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4+ T-cells, HCMV clearance and progressive reduction in activated TFH cells. The main differences between healthy and transplanted patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated TFH cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplanted patients. A preliminary analysis of the specificity of the activated TFH cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defense during primary infection is conferred by antibodies produced through the interaction of TFH cells and B cells of germinal centers, resulting in differentiation of B cells into antibody producing plasma cells.

ACS Style

Francesca Bruno; Chiara Fornara; Paola Zelini; Milena Furione; Elena Carrara; Lucia Scaramuzzi; Ilaria Cane; Federico Mele; Federica Sallusto; Daniele Lilleri; Giuseppe Gerna. Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients. Journal of General Virology 2016, 97, 1928 -1941.

AMA Style

Francesca Bruno, Chiara Fornara, Paola Zelini, Milena Furione, Elena Carrara, Lucia Scaramuzzi, Ilaria Cane, Federico Mele, Federica Sallusto, Daniele Lilleri, Giuseppe Gerna. Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients. Journal of General Virology. 2016; 97 (8):1928-1941.

Chicago/Turabian Style

Francesca Bruno; Chiara Fornara; Paola Zelini; Milena Furione; Elena Carrara; Lucia Scaramuzzi; Ilaria Cane; Federico Mele; Federica Sallusto; Daniele Lilleri; Giuseppe Gerna. 2016. "Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients." Journal of General Virology 97, no. 8: 1928-1941.

Comparative study
Published: 05 January 2016 in Journal of Medical Virology
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To discriminate between primary (PI) and remote (RI) human cytomegalovirus (HCMV) infection, several immunological parameters were monitored for a two-year period in 53 pregnant women with PI, and 33 pregnant women experiencing HCMV PI at least 5 years prior. Cytokine (IFN-γ and IL-2) production by and phenotype (effector/memory CD45RA+) of HCMV-specific CD4+ and CD8+ T-cells as well as the lymphoproliferative responses (LPR) were evaluated, with special reference to the comparison between a group of women transmitting (T) and a group of non-transmitting (NT) the infection to fetus. While HCMV-specific CD4+ T-cells reached at 90d p.i. values comparable to RI, CD8+ T–cells reached at 60d p.i. levels significantly higher and persisting throughout the entire follow-up. Instead, IL-2 production and lymphoproliferative responses were lower in PI than RI for the entire follow-up period. Effector memory CD45RA+ CD4+ and CD8+ HCMV-specific T-cells increased until 90d p.i., reaching and maintaining levels higher than RI. The comparison between T and NT women showed that, at 30d p.i., in NT women there was a significantly higher IL-2 production by HCMV-specific CD4+ T-cells, and at 60d p.i. a significantly higher frequency of both specific CD4+ and CD8+ CD45RA+ T-cells. HCMV T-cell response appears to correlate with virus transmission to fetus and some parameters (CD4+ lymphoproliferation, and frequency of HCMV-specific CD8+ IL2+ T-cells) may help in dating PI during pregnancy. This article is protected by copyright. All rights reserved

ACS Style

Chiara Fornara; Milena Furione; Alessia Arossa; Giuseppe Gerna; Daniele Lilleri. Comparative magnitude and kinetics of human cytomegalovirus-specific CD4+ and CD8+ T-cell responses in pregnant women with primary versus remote infection and in transmitting versus non-transmitting mothers: Its utility for dating primary infection in pre. Journal of Medical Virology 2016, 88, 1238 -1246.

AMA Style

Chiara Fornara, Milena Furione, Alessia Arossa, Giuseppe Gerna, Daniele Lilleri. Comparative magnitude and kinetics of human cytomegalovirus-specific CD4+ and CD8+ T-cell responses in pregnant women with primary versus remote infection and in transmitting versus non-transmitting mothers: Its utility for dating primary infection in pre. Journal of Medical Virology. 2016; 88 (7):1238-1246.

Chicago/Turabian Style

Chiara Fornara; Milena Furione; Alessia Arossa; Giuseppe Gerna; Daniele Lilleri. 2016. "Comparative magnitude and kinetics of human cytomegalovirus-specific CD4+ and CD8+ T-cell responses in pregnant women with primary versus remote infection and in transmitting versus non-transmitting mothers: Its utility for dating primary infection in pre." Journal of Medical Virology 88, no. 7: 1238-1246.

Journal article
Published: 01 March 2015 in Journal of Clinical Virology
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Human cytomegalovirus infections are mostly asymptomatic in infants and young children, while they are often associated with overt clinical symptoms in adults.

ACS Style

Chiara Fornara; Milena Furione; Daniele Lilleri; Ilaria Cane; M. Grazia Revello; Maurizio Zavattoni; Giuseppe Gerna. Primary human cytomegalovirus infections: Kinetics of ELISA-IgG and neutralizing antibody in pauci/asymptomatic pregnant women vs symptomatic non-pregnant subjects. Journal of Clinical Virology 2015, 64, 45 -51.

AMA Style

Chiara Fornara, Milena Furione, Daniele Lilleri, Ilaria Cane, M. Grazia Revello, Maurizio Zavattoni, Giuseppe Gerna. Primary human cytomegalovirus infections: Kinetics of ELISA-IgG and neutralizing antibody in pauci/asymptomatic pregnant women vs symptomatic non-pregnant subjects. Journal of Clinical Virology. 2015; 64 ():45-51.

Chicago/Turabian Style

Chiara Fornara; Milena Furione; Daniele Lilleri; Ilaria Cane; M. Grazia Revello; Maurizio Zavattoni; Giuseppe Gerna. 2015. "Primary human cytomegalovirus infections: Kinetics of ELISA-IgG and neutralizing antibody in pauci/asymptomatic pregnant women vs symptomatic non-pregnant subjects." Journal of Clinical Virology 64, no. : 45-51.

Comparative study
Published: 01 February 2015 in Journal of General Virology
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The comparative long-term kinetics of human cytomegalovirus (HCMV) load and HCMV-specific antibody responses in the immunocompetent and immunocompromised solid-organ transplanted host during primary HCMV infection was investigated. In total, 40 immunocompetent subjects and 17 transplanted patients were examined for viral load as well as for IgG antibody responses to HCMV glycoproteins gH/gL/pUL128L, gH/gL and gB, and neutralizing antibodies in ARPE-19 epithelial cells and human fibroblasts. In parallel, the CD4(+) and CD8(+) HCMV-specific T-cell responses were determined by cytokine flow cytometry. Transplanted patients reached significantly higher viral DNA peaks, which persisted longer than in immunocompetent subjects. The ELISA-IgG responses to the pentamer, gH/gL and gB were significantly higher in primary infections of the immunocompetent until six months after onset, with the two antibody levels then overlapping from six to 12 months. Antibody levels neutralizing infection of epithelial cells were significantly higher in transplanted patients after six months, persisting for up to a year after transplantation. This trend was not observed for antibodies neutralizing infection of human fibroblasts, which showed higher titres in the immunocompetent over the entire one-year follow-up. In conclusion, in immunocompromised patients the viral load peak was much higher, while the neutralizing antibody response exceeded that detected in the immunocompetent host starting six months after onset of follow-up, often concomitantly with a lack of specific CD4(+) T cells. In this setting, the elevated antibody response occurred in the presence of differentiated follicular helper T cells in the blood, which decreased in number as did antibody titres upon reappearance of HCMV-specific CD4(+) T cells.

ACS Style

Giuseppe Gerna; Daniele Lilleri; Chiara Fornara; Francesca Bruno; Elisa Gabanti; Ilaria Cane; Milena Furione; M. Grazia Revello. Differential kinetics of human cytomegalovirus load and antibody responses in primary infection of the immunocompetent and immunocompromised host. Journal of General Virology 2015, 96, 360 -369.

AMA Style

Giuseppe Gerna, Daniele Lilleri, Chiara Fornara, Francesca Bruno, Elisa Gabanti, Ilaria Cane, Milena Furione, M. Grazia Revello. Differential kinetics of human cytomegalovirus load and antibody responses in primary infection of the immunocompetent and immunocompromised host. Journal of General Virology. 2015; 96 (2):360-369.

Chicago/Turabian Style

Giuseppe Gerna; Daniele Lilleri; Chiara Fornara; Francesca Bruno; Elisa Gabanti; Ilaria Cane; Milena Furione; M. Grazia Revello. 2015. "Differential kinetics of human cytomegalovirus load and antibody responses in primary infection of the immunocompetent and immunocompromised host." Journal of General Virology 96, no. 2: 360-369.

Journal article
Published: 18 September 2014 in Journal of Clinical Immunology
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Following primary human cytomegalovirus (HCMV) infection, both humoral and T-cell-mediated immune responses develop in immunocompetent subjects. However, while antibodies may be measured by different methodologies, the T-cell-mediated response remains to be analyzed in its polyfunctional aspects, in view of defining (following different stimuli) the optimal assay to monitor the HCMV-specific T-cell response in HCMV-seropositive subjects. In a group of 30 HCMV-seropositive adults, T-cell response revealed by the HCMV-infected dendritic cell (iDC) stimulus was compared with those given by the HCMV-infected cell lysate (iCL), and by a 34-peptide pool (PP). All HCMV-seropositive subjects showed presence of both HCMV-specific CD4(+) and CD8(+) T-cells in peripheral blood following iDC stimulation. One subject did not respond to PP. As compared to iDC, the number of HCMV-specific stimulated T-cells/μl blood was slightly lower for iCL (P = 0.195) and significantly lower for PP (P = 0.001). Polyfunctional analysis of the T-cell response indicated that the lower number of CD4(+) T-cells stimulated by iCL was due to the bifunctional (IFN-γ(+) TNF-α(+)) and CD40L-negative T-cell reduction, while the reduction in specific PP-stimulated CD8(+) T-cells was attributable to the reduction in tri-(IFN-γ(+) TNF-α(+) IL2(+)), bi-(IFN-γ(+) TNF-α(+)) and mono-(IFN-γ(+)) functional T-cells. In addition, 15/30 (50 %) subjects showed a CD4(+) cross-response to PP, and 11/30 (37 %) a CD8(+) cross-response to iCL. HCMV-specific stimulus given by iDC is not significantly different from that of iCL on CD4(+) and is significantly superior to that of PP on CD8+ T-cells. However, iCL may contribute significantly to CD8(+), and PP to CD4(+) T-cell stimulation.

ACS Style

Elisa Gabanti; Francesca Bruno; Chiara Fornara; Stefano Bernuzzi; Daniele Lilleri; Giuseppe Gerna. Polyfunctional Analysis of Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ Memory T-Cells in HCMV-Seropositive Healthy Subjects Following Different Stimuli. Journal of Clinical Immunology 2014, 34, 999 -1008.

AMA Style

Elisa Gabanti, Francesca Bruno, Chiara Fornara, Stefano Bernuzzi, Daniele Lilleri, Giuseppe Gerna. Polyfunctional Analysis of Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ Memory T-Cells in HCMV-Seropositive Healthy Subjects Following Different Stimuli. Journal of Clinical Immunology. 2014; 34 (8):999-1008.

Chicago/Turabian Style

Elisa Gabanti; Francesca Bruno; Chiara Fornara; Stefano Bernuzzi; Daniele Lilleri; Giuseppe Gerna. 2014. "Polyfunctional Analysis of Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ Memory T-Cells in HCMV-Seropositive Healthy Subjects Following Different Stimuli." Journal of Clinical Immunology 34, no. 8: 999-1008.

Research article
Published: 28 August 2014 in PLOS ONE
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In solid-organ transplant recipients (SOTR) the protective role of human cytomegalovirus (HCMV)-specific CD4+, CD8+ and γδ T-cells vs. HCMV reactivation requires better definition. The aim of this study was to investigate the relevant role of HCMV-specific CD4+, CD8+ and γδ T-cells in different clinical presentations during the post-transplant period. Thirty-nine SOTR underwent virologic and immunologic follow-up for about 1 year after transplantation. Viral load was determined by real-time PCR, while immunologic monitoring was performed by measuring HCMV-specific CD4+ and CD8+ T cells (following stimulation with autologous HCMV-infected dendritic cells) and γδ T-cells by flow cytometry. Seven patients had no infection and 14 had a controlled infection, while both groups maintained CD4+ T-cell numbers above the established cut-off (0.4 cell/µL blood). Of the remaining patients, 9 controlled the infection temporarily in the presence of HCMV-specific CD8+ only, until CD4+ T-cell appearance; while 9 had to be treated preemptively due to a viral load greater than the established cut-off (3×105 DNA copies/mL blood) in the absence of specific CD4+ T-cells. Polyfunctional CD8+ T-cells as well as Vδ2− γδ T-cells were not associated with control of infection. In conclusion, in the absence of HCMV-specific CD4+ T-cells, no long-term protection is conferred to SOTR by either HCMV-specific CD8+ T-cells alone or Vδ2− γδ T-cell expansion.

ACS Style

Elisa Gabanti; Francesca Bruno; Daniele Lilleri; Chiara Fornara; Paola Zelini; Ilaria Cane; Clara Migotto; Eleonora Sarchi; Milena Furione; Giuseppe Gerna. Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ T Cells Are Both Required for Prevention of HCMV Disease in Seropositive Solid-Organ Transplant Recipients. PLOS ONE 2014, 9, e106044 .

AMA Style

Elisa Gabanti, Francesca Bruno, Daniele Lilleri, Chiara Fornara, Paola Zelini, Ilaria Cane, Clara Migotto, Eleonora Sarchi, Milena Furione, Giuseppe Gerna. Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ T Cells Are Both Required for Prevention of HCMV Disease in Seropositive Solid-Organ Transplant Recipients. PLOS ONE. 2014; 9 (8):e106044.

Chicago/Turabian Style

Elisa Gabanti; Francesca Bruno; Daniele Lilleri; Chiara Fornara; Paola Zelini; Ilaria Cane; Clara Migotto; Eleonora Sarchi; Milena Furione; Giuseppe Gerna. 2014. "Human Cytomegalovirus (HCMV)-Specific CD4+ and CD8+ T Cells Are Both Required for Prevention of HCMV Disease in Seropositive Solid-Organ Transplant Recipients." PLOS ONE 9, no. 8: e106044.

Review
Published: 01 March 2014 in Early Human Development
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Maria Grazia Revello; Chiara Fornara; Alessia Arossa; Paola Zelini; Daniele Lilleri. Role of human cytomegalovirus (HCMV)-specific antibody in HCMV-infected pregnant women. Early Human Development 2014, 90, S32 -S34.

AMA Style

Maria Grazia Revello, Chiara Fornara, Alessia Arossa, Paola Zelini, Daniele Lilleri. Role of human cytomegalovirus (HCMV)-specific antibody in HCMV-infected pregnant women. Early Human Development. 2014; 90 ():S32-S34.

Chicago/Turabian Style

Maria Grazia Revello; Chiara Fornara; Alessia Arossa; Paola Zelini; Daniele Lilleri. 2014. "Role of human cytomegalovirus (HCMV)-specific antibody in HCMV-infected pregnant women." Early Human Development 90, no. : S32-S34.

Observational study
Published: 30 June 2013 in The new microbiologica
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Daniele Lilleri; Giuseppe Gerna; Francesca Bruno; Paola Draghi; Elisa Gabanti; Chiara Fornara; Federica Meloni. Systemic and local human cytomegalovirus-specific T-cell response in lung transplant recipients. The new microbiologica 2013, 36, 1 .

AMA Style

Daniele Lilleri, Giuseppe Gerna, Francesca Bruno, Paola Draghi, Elisa Gabanti, Chiara Fornara, Federica Meloni. Systemic and local human cytomegalovirus-specific T-cell response in lung transplant recipients. The new microbiologica. 2013; 36 (3):1.

Chicago/Turabian Style

Daniele Lilleri; Giuseppe Gerna; Francesca Bruno; Paola Draghi; Elisa Gabanti; Chiara Fornara; Federica Meloni. 2013. "Systemic and local human cytomegalovirus-specific T-cell response in lung transplant recipients." The new microbiologica 36, no. 3: 1.

Journal article
Published: 17 August 2011 in Journal of Clinical Immunology
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The T-cell response to human cytomegalovirus (HCMV) primary infection was analyzed in 27 pregnant women during the first year after primary HCMV infection. Pregnant women with remote HCMV infection were enrolled as controls. Interferon-γ-producing T cells were readily detected at levels comparable (CD4+) or higher (CD8+) than controls, whereas the CD4+ and CD8+ lymphoproliferative response as well as IL-2 production was significantly reduced with respect to controls for at least 9 months after infection. In addition, CD45RA re-expression as well as cytotoxic T lymphocyte activity and perforin expression were the major components of the adaptive CD4+ and CD8+ T-cell immune response, while Vδ2− γδ T-cell expansion in response to HCMV infection followed kinetics similar to that of CD8+ T cells. Reduced CD45RA re-expression directly correlated with HCMV transmission to the fetus, thus providing an important prognostic parameter.

ACS Style

Chiara Fornara; Daniele Lilleri; M. Grazia Revello; Milena Furione; Maurizio Zavattoni; Elisa Lenta; Giuseppe Gerna. Kinetics of Effector Functions and Phenotype of Virus-Specific and γδ T Lymphocytes in Primary Human Cytomegalovirus Infection During Pregnancy. Journal of Clinical Immunology 2011, 31, 1054 -1064.

AMA Style

Chiara Fornara, Daniele Lilleri, M. Grazia Revello, Milena Furione, Maurizio Zavattoni, Elisa Lenta, Giuseppe Gerna. Kinetics of Effector Functions and Phenotype of Virus-Specific and γδ T Lymphocytes in Primary Human Cytomegalovirus Infection During Pregnancy. Journal of Clinical Immunology. 2011; 31 (6):1054-1064.

Chicago/Turabian Style

Chiara Fornara; Daniele Lilleri; M. Grazia Revello; Milena Furione; Maurizio Zavattoni; Elisa Lenta; Giuseppe Gerna. 2011. "Kinetics of Effector Functions and Phenotype of Virus-Specific and γδ T Lymphocytes in Primary Human Cytomegalovirus Infection During Pregnancy." Journal of Clinical Immunology 31, no. 6: 1054-1064.