Maternal CD4
            <sup>+</sup>
            T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission

Bialas, Kristy M.; Tanaka, Takayuki; Tran, Dollnovan; Varner, Valerie; Rosa, Eduardo Cisneros De La; Chiuppesi, Flavia; Wussow, Felix; Kattenhorn, Lisa; Macri, Sheila Cummings Sm; Kunz, Erika L.; Estroff, Judy A.; Kirchherr, Jennifer; Yue, Yujuan; Fan, Qihua; Lauck, Michael; O’Connor, David H.; Hall, Allison; Álvarez, Xavier; Diamond, Don J.; Barry, Peter A.; Kaur, Amitinder; Permar, Sallie R.

doi:10.1073/pnas.1511526112

Cited by 95 publications

(157 citation statements)

References 48 publications

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“…Such a neutralizing antibody response was also detected in the saliva of immunized animals and reached serum titres comparable to those found in HCMV hyperimmune globulin preparations [97]. In addition, using this non-human primate model, it was shown that CD4 + depletion at the time of rhesus virus inoculation induced both a reduced and delayed neutralizing antibody response [98].…”

Section: Development Of An Hcmv Vaccine: Potential Role Of the Pcsupporting

confidence: 62%

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The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Gerna

Revello

Baldanti

et al. 2017

Journal of General Virology

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Between the 1980s and 1990s, three assays were developed for diagnosis of human cytomegalovirus (HCMV) infections: leuko (L)-antigenemia, L-viremia and L-DNAemia, detecting viral protein pp65, infectious virus and viral DNA, respectively, in circulating leukocytes Repeated initial attempts to reproduce the three assays in vitro using laboratory-adapted strains and infected cell cultures were consistently unsuccessful. Results were totally reversed when wild-type HCMV strains were used to infect either fibroblasts or endothelial cells. Careful analysis and sequencing of plaque-purified viruses from recent clinical isolates drew attention to the ULb¢ region of the HCMV genome. Using bacterial artificial chromosome technology, it was shown by both gain-of-function and loss-of-function experiments that UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. In addition, a number of clinical isolates passaged in human fibroblasts had lost both properties (leuko-tropism and endothelial cell-tropism) when displaying a mutation in the UL131-128 locus

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Section: Development Of An Hcmv Vaccine: Potential Role Of the Pcsupporting

confidence: 62%

“…Finally, a neutralizing mAb to gH/gL was found to be protective in the guinea pig model of congenital infection [121]. However, concerns have been raised about the ability of the guinea pig model to predict the outcome of clinical trials [98,122].…”

Section: Development Of An Hcmv Vaccine: Potential Role Of the Pcmentioning

confidence: 99%

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Gerna

Revello

Baldanti

et al. 2017

Journal of General Virology

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“…We reported a similar finding in our newly developed rhesus monkey model of cCMV transmission, which demonstrated that pregnant monkeys lacking peripheral CD4 + T-cells had high rates of placental rhesus CMV transmission, potentially attributable to the observed delay in the maternal CMV-specific neutralizing antibody response [23]. Thus, it is plausible that the effect of HIV on CD4 + T-cells may similarly impair the functional CMV-specific antibody responses, leading to enhanced cCMV transmission.…”

supporting

confidence: 74%

“…However, this study suggests that preexposure provision of passive antibodies that mediate potent epithelial cell could provide enhanced protection. Alternatively, as we did not study the role of T-cell immunity in this population, we cannot rule out the possibility that protection against cCMV transmission is dependent on a robust T-cell-mediated memory response, particularly the CD4 + T-cell response [20,23], which is impaired in women with chronic HIV/CMV coinfection. This work suggests that strategies to enhance CMV-specific immunity in seropositive mothers may help to impede secondary cCMV transmission.…”

Section: Discussionmentioning

confidence: 97%

Maternal Antibody Responses and Nonprimary Congenital Cytomegalovirus Infection of HIV-1–Exposed Infants

et al. 2016

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Risk of congenital cytomegalovirus (cCMV) transmission is highly dependent on the presence of preexisting maternal immunity, with the lowest rates observed in CMV-seroimmune populations. Among infants of CMV-seroimmune women, those who are exposed to human immunodeficiency virus (HIV) have an increased risk of acquiring cCMV infection as compared to HIV-unexposed infants. To better understand the risk factors of nonprimary cCMV transmission in HIV-infected women, we performed a casecontrol study in which CMV-specific plasma antibody responses from 19 CMV-transmitting and 57 CMV-nontransmitting women with chronic CMV/HIV coinfection were evaluated for the ability to predict the risk of cCMV infection. Primary multivariable conditional logistic regression analysis revealed an association between epithelial-tropic CMV neutralizing titers and a reduced risk of cCMV transmission (odds ratio [OR], 0.18; 95% confidence interval [CI], .03-.93; P = .04), although this effect was not significant following correction for multiple comparisons (false-discovery rate, 0.12). Exploratory analysis of the CMV specificity of plasma antibodies revealed that immunoglobulin G (IgG) responses against the glycoprotein B (gB) neutralizing epitope AD-2 had a borderline association with low risk of transmission (OR, 0.72; 95% CI, .51-1.00; P = .05), although this was not confirmed in a post hoc plasma anti-AD-2 IgG blocking assay. Our data suggest that maternal neutralizing antibody responses may play a role in protection against cCMV in HIV/CMV-coinfected populations.

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“…Recently, several studies assessed the role of CMV CMI in pregnant women. Bialas and colleagues showed that CD4 ϩ T-cell depletion in infected pregnant rhesus macaques led to dismal and more severe outcomes compared with those of immunocompetent pregnant primates, thus suggesting a protective role of CD4 ϩ T cells with respect to cCMV (31). A previous study of primary-infected pregnant women had already identified CMV-specific CD4 ϩ T cells as key players in maternal CMV infection, and a low lymphoproliferative response associated significantly with an increased risk of congenital transmission (32).…”

Section: Maternal Cmv-specific T-cell Immunity As a Marker For Intraumentioning

confidence: 99%

Testing for Cytomegalovirus in Pregnancy

et al. 2017

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Congenital cytomegalovirus (CMV) infection represents a relevant cause of deafness and neurological damage in newborns. Intrauterine CMV transmission might result after primary or nonprimary infections, though at different rates (30% versus 0.2%, respectively). At present, a prenatal diagnosis of CMV infection is based mainly on maternal serology, the detection of CMV-DNA in amniotic fluid and fetal blood, and ultrasound (US) and magnetic resonance imaging (MRI). Recent evidences suggest that congenital CMV infection may be an immune-mediated disease and that evaluation of humoral and especially T-cell immunities may improve the overall prenatal diagnosis. This review summarizes the most recent advancements in the diagnosis of maternal and prenatal CMV infections.KEYWORDS human cytomegalovirus, laboratory assays, congenital infections, IgG avidity, CMV-ELISPOT, CMV-QuantiFERON, immunoserology, imaging T he human cytomegalovirus (CMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunocompromised patients and congenitally infected fetuses and newborns, resulting in a broad range of disabilities, including sensorineural hearing loss (SNHL), visual impairment, and motor and cognitive deficits. Other transient symptoms of congenital CMV infection (cCMV) may include hepatosplenomegaly, thrombocytopenia, and jaundice. The global prevalence of cCMV has been estimated at 0.7% (1), and fetal CMV transmission may arise from a maternal primary or nonprimary infection. The highest rate of cCMV occurs after primary infections in seronegative mothers (30 to 40%), while nonprimary infections, including CMV reactivations or reinfections, result in cCMV in 0.2 to 2% of cases, suggesting that preconceptional immunity may play a role in preventing intrauterine transmission (2). If the main burden of congenital infections in Europe and North America results from primary infections, then nonprimary infections represent the main cause of cCMV in developing countries or in poor socioeconomical contexts, since the seroprevalences among the resident populations are much higher (3). The severities of infections in neonates and infants are highly variable. It has been estimated that 10 to 15% of congenitally infected neonates are symptomatic at birth, and 40 to 58% of them will experience permanent long-term sequelae. Moreover, 13.5% of children with asymptomatic infections will develop late-onset sequelae, mainly consisting of hearing impairments and neurologic deficits. The effectiveness of antiviral treatment during pregnancy is still debated. Most of the concerns are related to the potential genotoxicity and teratogenicity of the drugs. The clinical benefits of CMV-specific hyperimmune globulin treatment are also disputed, due to discordant results obtained from different studies (4,5).In the last decade, major efforts have been made to improve the early laboratory diagnosis of maternal and fetal infections. Despite these efforts, at present, many countries in the world have not yet adopted a consolidate...

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Maternal CD4 ⁺ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission

Cited by 95 publications

References 48 publications

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Maternal Antibody Responses and Nonprimary Congenital Cytomegalovirus Infection of HIV-1–Exposed Infants

Testing for Cytomegalovirus in Pregnancy

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Maternal CD4 + T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission

Cited by 95 publications

References 48 publications

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Maternal Antibody Responses and Nonprimary Congenital Cytomegalovirus Infection of HIV-1–Exposed Infants

Testing for Cytomegalovirus in Pregnancy

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Maternal CD4 ⁺ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission