Publications by authors named "William J Britt"

115 Publications

NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection.

J Exp Med 2021 May;218(5)

Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.

Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti-IFN-γ antibodies.
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http://dx.doi.org/10.1084/jem.20201503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918636PMC
May 2021

Virological Characteristics of Hospitalized Children With SARS-CoV-2 Infection.

Pediatrics 2021 05 23;147(5). Epub 2021 Feb 23.

Departments of Pediatrics and.

Background And Objectives: In children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, virological characteristics and correlation with disease severity have not been extensively studied. The primary objective in this study is to determine the correlation between SARS-CoV-2 viral load (VL) in infected children with age, disease severity, and underlying comorbidities.

Methods: Children <21 years, screened for SARS-CoV-2 at the time of hospitalization, who tested positive by polymerase chain reaction were included in this study. VL at different sites was determined and compared between groups.

Results: Of the 102 children included in this study, 44% of the cohort had asymptomatic infection, and children with >1 comorbidity were the most at risk for severe disease. VL in children with symptomatic infection was significantly higher than in children with asymptomatic infection (3.0 × 10 vs 7.2 × 10 copies per mL; = .001). VL in the respiratory tract was significantly higher in children <1 year, compared with older children (3.3 × 10 vs 1.3 × 10 copies per mL respectively; < .0001), despite most infants presenting with milder illness. Besides the respiratory tract, SARS-CoV-2 RNA was also detectable in samples from the gastrointestinal tract (saliva and rectum) and blood. In 13 children for whom data on duration of polymerase chain reaction positivity was available, 12 of 13 tested positive 2 weeks after initial diagnosis, and 6 of 13 continued to test positive 4 weeks after initial diagnosis.

Conclusions: In hospitalized children with SARS-CoV-2, those with >1 comorbid condition experienced severe disease. SARS-CoV-2 VL in the respiratory tract is significantly higher in children with symptomatic disease and children <1 year of age.
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http://dx.doi.org/10.1542/peds.2020-037812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086003PMC
May 2021

Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines.

Methods Mol Biol 2021 ;2244:403-463

Departments of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA.

Human cytomegalovirus is the largest human herpesvirus and shares many core features of other herpesviruses such as tightly regulated gene expression during genome replication and latency as well as the establishment of lifelong persistence following infection. In contrast to stereotypic clinical syndromes associated with alpha-herpesvirus infections, almost all primary HCMV infections are asymptomatic and acquired early in life in most populations in the world. Although asymptomatic in most individuals, HCMV is a major cause of disease in hosts with deficits in adaptive and innate immunity such as infants who are infected in utero and allograft recipients following transplantation. Congenital HCMV is a commonly acquired infection in the developing fetus that can result in a number of neurodevelopmental abnormalities. Similarly, HCMV is a major cause of disease in allograft recipients in the immediate and late posttransplant period and is thought to be a major contributor to chronic allograft rejection. Even though HCMV induces robust innate and adaptive immune responses, it also encodes a vast array of immune evasion functions that are thought aid in its persistence. Immune correlates of protective immunity that prevent or modify intrauterine HCMV infection remain incompletely defined but are thought to consist primarily of adaptive responses in the pregnant mother, thus making congenital HCMV a potentially vaccine modifiable disease. Similarly, HCMV infection in allograft recipients is often more severe in recipients without preexisting adaptive immunity to HCMV. Thus, there has been a considerable effort to modify HCMV specific immunity in transplant recipient either through active immunization or passive transfer of adaptive effector functions. Although efforts to develop an efficacious vaccine and/or passive immunotherapy to limit HCMV disease have been underway for nearly six decades, most have met with limited success at best. In contrast to previous efforts, current HCMV vaccine development has relied on observations of unique properties of HCMV in hopes of reproducing immune responses that at a minimum will be similar to that following natural infection. However, more recent findings have suggested that immunity following naturally acquired HCMV infection may have limited protective activity and almost certainly, is not sterilizing. Such observations suggest that either the induction of natural immunity must be specifically tailored to generate protective activity or alternatively, that providing targeted passive immunity to susceptible populations could be prove to be more efficacious.
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http://dx.doi.org/10.1007/978-1-0716-1111-1_19DOI Listing
April 2021

Localization of the WD repeat-containing protein 5 to the Virion Assembly Compartment Facilitates Human Cytomegalovirus Assembly.

J Virol 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

We previously reported that human cytomegalovirus (HCMV) utilizes the cellular protein WD repeat-containing protein 5 (WDR5) to facilitate capsid nuclear egress. Here, we further show that HCMV infection results in WDR5 localization in a juxtanuclear region, and that its localization to this cellular site is associated with viral replication and late viral gene expression. Furthermore, WDR5 accumulated in the virion assembly compartment (vAC) and co-localized with vAC markers of gamma-tubulin (γ-tubulin), early endosomes, and viral vAC marker proteins pp65, pp28, and glycoprotein B (gB). WDR5 co-immunoprecipitated with multiple virion proteins, including MCP, pp150, pp65, pIRS1, and pTRS1, which may explain WDR5 accumulation in the vAC during infection. WDR5 fractionated with virions either in the presence or absence of Triton X-100 and was present in purified viral particles, suggesting that WDR5 was incorporated into HCMV virions. Thus, WDR5 localized to the vAC and was incorporated into virions, raising the possibility that in addition to capsid nuclear egress, WDR5 could also participate in cytoplasmic HCMV virion morphogenesis. Human cytomegalovirus (HCMV) has a large (∼235-kb) genome that contains over 170 ORFs and exploits numerous cellular factors to facilitate its replication. In the late phase of HCMV infection cytoplasmic membranes are reorganized to establish the virion assembly compartment (vAC), which has been shown to necessary for efficient assembly of progeny virions. We previously reported that WDR5 facilitates HCMV nuclear egress. Here, we show that WDR5 is localized to the vAC and incorporated into virions, perhaps contributing to efficient virion maturation. Thus, findings in this study identified a potential role for WDR5 in HCMV assembly in the cytoplasmic phase of virion morphogenesis.
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http://dx.doi.org/10.1128/JVI.02101-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103678PMC
January 2021

Human Cytomegalovirus Envelope Protein gpUL132 Regulates Infectious Virus Production through Formation of the Viral Assembly Compartment.

mBio 2020 09 29;11(5). Epub 2020 Sep 29.

Department of Microbiology, School of Medicine, University of Alabama in Birmingham, Birmingham, Alabama, USA

The human cytomegalovirus (HCMV) UL132 open reading frame encodes a 270-amino-acid type I envelope glycoprotein, gpUL132. The deletion of UL132 (ΔUL132) from the HCMV genome results in a pronounced deficit in virus yield, with an approximately 2-log decrease in the production of infectious virus compared to the wild-type (WT) virus. Characterization of the ΔUL132 mutant virus indicated that it was less infectious with a high particle-to-infectious unit ratio and an altered composition of virion proteins compared to the WT virus. In addition, the viral assembly compartment (AC) failed to form in cells infected with the ΔUL132 mutant virus. The expression of gpUL132 in rescued the defects in the morphogenesis of the AC in cells infected with the ΔUL132 mutant virus and in infectious virus production. Furthermore, using cell lines expressing chimeric proteins, we demonstrated that the cytosolic domain of gpUL132 was sufficient to rescue AC formation and WT levels of virus production. Progeny virions from ΔUL132-infected cells expressing the cytosolic domain of gpUL132 exhibited particle-to-infectious unit ratios similar to those of the WT virus. Together, our findings argue that gpUL132 is essential for HCMV AC formation and the efficient production of infectious particles, thus highlighting the importance of this envelope protein for the virus-induced reorganization of intracellular membranes and AC formation in the assembly of infectious virus. Following infection of permissive cells, human cytomegalovirus (HCMV) induces the reorganization of intracellular membranes resulting in the formation of a distinctive membranous compartment in the cytoplasm of infected cells. This compartment has been designated the viral assembly compartment (AC) and is thought to be a site for cytoplasmic virion assembly and envelopment. In this study, we have demonstrated that a single virion envelope glycoprotein is essential for AC formation in infected cells, and in its absence, there is a significant decrease in the production of infectious virions. These findings are consistent with those from other studies that have demonstrated the importance of host cell proteins in the formation of the AC and demonstrate a critical role of a single virion protein in AC formation and the efficient assembly of infectious virus.
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http://dx.doi.org/10.1128/mBio.02044-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527726PMC
September 2020

Comprehensive evaluation of risk factors for neonatal hearing loss in a large Brazilian cohort.

J Perinatol 2021 Feb 3;41(2):315-323. Epub 2020 Sep 3.

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.

Objectives: To determine the incidence and risk factors of hearing loss (HL) in Brazilian neonates.

Study Design: 11,900 neonates were screened for hearing and congenital CMV (cCMV). Low and high-risk babies who did not pass their hearing screening and infants with cCMV were scheduled for a diagnostic audiologic evaluation.

Results: The incidence of HL was 2 per 1000 live-born infants (95% CI: 1-3). HL was higher in high-risk neonates than in low risk babies (18.6 vs. 0.3/1000 live births, respectively). Among infants exposed to isolated risk factors, association of HL with craniofacial abnormalities/syndromes (RR = 24.47; 95% CI: 5.9-100.9) and cCMV (RR = 9.54; 95% CI: 3.3-27.7) were observed. HL was 20 to 100-fold more likely in neonates exposed to ototoxic drugs in combination with cCMV or craniofacial/congenital anomalies.

Conclusions: Strategies for the prevention of cCMV and exposure to ototoxic drugs may decrease the incidence of HL in this population.
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http://dx.doi.org/10.1038/s41372-020-00807-8DOI Listing
February 2021

Cell Fusion Induced by a Fusion-Active Form of Human Cytomegalovirus Glycoprotein B (gB) Is Inhibited by Antibodies Directed at Antigenic Domain 5 in the Ectodomain of gB.

J Virol 2020 08 31;94(18). Epub 2020 Aug 31.

Virologisches Institut, Klinische und Molekulare Virologie, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen, Germany

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that can cause severe clinical disease in allograft recipients and infants infected Virus-neutralizing antibodies defined have been proposed to confer protection against HCMV infection, and the virion envelope glycoprotein B (gB) serves as a major target of neutralizing antibodies. The viral fusion protein gB is nonfusogenic on its own and requires glycoproteins H (gH) and L (gL) for membrane fusion, which is in contrast to requirements of related class III fusion proteins, including vesicular stomatitis virus glycoprotein G (VSV-G) or baculovirus gp64. To explore requirements for gB's fusion activity, we generated a set of chimeras composed of gB and VSV-G or gp64, respectively. These gB chimeras were intrinsically fusion active and led to the formation of multinucleated cell syncytia when expressed in the absence of other viral proteins. Utilizing a panel of virus-neutralizing gB-specific monoclonal antibodies (MAbs), we could demonstrate that syncytium formation of the fusogenic gB/VSV-G chimera can be significantly inhibited by only a subset of neutralizing MAbs which target antigenic domain 5 (AD-5) of gB. This observation argues for differential modes of action of neutralizing anti-gB MAbs and suggests that blocking the membrane fusion function of gB could be one mechanism of antibody-mediated virus neutralization. In addition, our data have important implications for the further understanding of the conformation of gB that promotes membrane fusion as well as the identification of structures in AD-5 that could be targeted by antibodies to block this early step in HCMV infection. HCMV is a major global health concern, and antiviral chemotherapy remains problematic due to toxicity of available compounds and the emergence of drug-resistant viruses. Thus, an HCMV vaccine represents a priority for both governmental and pharmaceutical research programs. A major obstacle for the development of a vaccine is a lack of knowledge of the nature and specificities of protective immune responses that should be induced by such a vaccine. Glycoprotein B of HCMV is an important target for neutralizing antibodies and, hence, is often included as a component of intervention strategies. By generation of fusion-active gB chimeras, we were able to identify target structures of neutralizing antibodies that potently block gB-induced membrane fusion. This experimental system provides an approach to screen for antibodies that interfere with gB's fusogenic activity. In summary, our data will likely contribute to both rational vaccine design and the development of antibody-based therapies against HCMV.
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http://dx.doi.org/10.1128/JVI.01276-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459561PMC
August 2020

Comparing Nasopharyngeal and Midturbinate Nasal Swab Testing for the Identification of Severe Acute Respiratory Syndrome Coronavirus 2.

Clin Infect Dis 2021 04;72(7):1253-1255

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Testing of paired midturbinate (MT) nasal and nasopharyngeal (NP) swabs, collected by trained personnel from 40 patients with coronavirus disease 2019 (COVID-19), showed that more NP (76/95 [80%]) than MT swabs tested positive (61/95 [64%]) (P = .02). Among samples collected a week after study enrollment, fewer MT than NP samples were positive (45% vs 76%; P = .001).
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http://dx.doi.org/10.1093/cid/ciaa882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337631PMC
April 2021

Phosphorylation of tegument protein pp28 contributes to trafficking to the assembly compartment in human cytomegalovirus infection.

J Microbiol 2020 Jul 27;58(7):624-631. Epub 2020 Jun 27.

Departments of Microbiology, Pediatrics, and Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Human cytomegalovirus (HCMV) UL99 encodes a late tegument protein pp28 that is essential for envelopment and production of infectious virus. This protein is localized to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) in transfected cells but it localizes to the cytoplasmic assembly compartment (AC) in HCMV-infected cells. Trafficking of pp28 to the AC is required for the assembly of infectious virus. The N-terminal domain (aa 1-61) of pp28 is sufficient for trafficking and function of the wild type protein during viral infection. However, residues required for authentic pp28 trafficking with the exception of the acidic cluster in the N-terminal domain of pp28 remain undefined. Monitoring protein migration on SDS-PAGE, we found that pp28 is phosphorylated in the virus-infected cells and dephosphorylated in the viral particles. By generating substitution mutants of pp28, we showed that three serine residues (aa 41-43) and a tyrosine residue (aa 34) account for its phosphorylation. The mutant forms of pp28 were localized to the plasma membrane as well as the ERGIC in transfected cells. Likewise, these mutant proteins were localized to the plasma membrane as well as the AC in virus-infected cells. These results suggested that phosphorylation of pp28 contributes to its intracellular trafficking and efficient viral assembly and incorporation.
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http://dx.doi.org/10.1007/s12275-020-0263-5DOI Listing
July 2020

Human Cytomegalovirus Infection in Women With Preexisting Immunity: Sources of Infection and Mechanisms of Infection in the Presence of Antiviral Immunity.

Authors:
William J Britt

J Infect Dis 2020 03;221(Suppl 1):S1-S8

Departments of Pediatrics, Microbiology, Neurobiology, University of Alabama School of Medicine, Birmingham, Alabama.

Human cytomegalovirus (HCMV) infection remains an important cause of neurodevelopmental sequelae in infants infected in utero. Unique to the natural history of perinatal HCMV infections is the occurrence of congenital HCMV infections (cCMV) in women with existing immunity to HCMV, infections that have been designated as nonprimary maternal infection. In maternal populations with a high HCMV seroprevalence, cCMV that follows nonprimary maternal infections accounts for 75%-90% of all cases of cCMV infections as well as a large proportion of infected infants with neurodevelopmental sequelae. Although considerable effort has been directed toward understanding immune correlates that can modify maternal infections and intrauterine transmission, the source of virus leading to nonprimary maternal infections and intrauterine transmission is not well defined. Previous paradigms that included reactivation of latent virus as the source of infection in immune women have been challenged by studies demonstrating acquisition and transmission of antigenically distinct viruses, a finding suggesting that reinfection through exposure to an exogenous virus is responsible for some cases of nonprimary maternal infection. Additional understanding of the source(s) of virus that leads to nonprimary maternal infection will be of considerable value in the development and testing of interventions such as vaccines designed to limit the incidence of cCMV in populations with high HCMV seroprevalence.
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http://dx.doi.org/10.1093/infdis/jiz464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057782PMC
March 2020

Correction to: Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2020 Feb 10;20(1):111. Epub 2020 Feb 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

After publication of the original article [1], we were notified that Fig. 3 has "Fig. 1" posted on the top of it and Figs. 4 and 5 have "Genomic Position" in a different spot.
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http://dx.doi.org/10.1186/s12879-020-4766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008528PMC
February 2020

Association of CMV genomic mutations with symptomatic infection and hearing loss in congenital CMV infection.

BMC Infect Dis 2019 Dec 10;19(1):1046. Epub 2019 Dec 10.

Department of Pediatrics, The University of Alabama School of Medicine, CHB 116, 1600 6th Avenue South, Birmingham, AL, USA.

Background: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and a leading cause of long-term neurological and sensory sequelae, the most common being sensorineural hearing loss (SNHL). Despite extensive research, clinical or laboratory markers to identify CMV infected children with increased risk for disease have not been identified. This study utilizes viral whole-genome next generation-sequencing (NGS) of specimens from congenitally infected infants to explore viral diversity and specific viral variants that may be associated with symptomatic infection and SNHL.

Methods: CMV DNA from urine specimens of 30 infants (17 asymptomatic, 13 symptomatic) was target enriched and next generation sequenced resulting in 93% coverage of the CMV genome allowing analysis of viral diversity.

Results: Variant frequency distribution was compared between children with symptomatic and asymptomatic cCMV and those with (n = 13) and without (n = 17) hearing loss. The CMV genes UL48A, UL88, US19 and US22 were found to have an increase in nucleotide diversity in symptomatic children; while UL57, UL20, UL104, US14, UL115, and UL35 had an increase in diversity in children with hearing loss. An analysis of single variant differences between symptomatic and asymptomatic children found UL55 to have the highest number, while the most variants associated with SNHL were in the RL11 gene family. In asymptomatic infants with SNHL, mutations were observed more frequently in UL33 and UL20.

Conclusion: CMV genomes from infected newborns can be mapped to 93% of the genome at a depth allowing accurate and reproducible analysis of polymorphisms for variant and gene discovery that may be linked to symptomatic and hearing loss outcomes.
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http://dx.doi.org/10.1186/s12879-019-4681-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905059PMC
December 2019

Contribution of Congenital Cytomegalovirus Infection to Permanent Hearing Loss in a Highly Seropositive Population: The Brazilian Cytomegalovirus Hearing and Maternal Secondary Infection Study.

Clin Infect Dis 2020 03;70(7):1379-1384

Department of Pediatrics, Otorhinolaryngology, and Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, Brazil.

Background: The exact contribution of congenital cytomegalovirus infection (cCMVI) to permanent hearing loss (HL) in highly seropositive populations is unknown. We determined the contribution of cCMVI to HL and estimated the effectiveness of newborn hearing screening (HS) in identifying neonates with CMV-related HL.

Methods: A total of 11 900 neonates born from a population with ≥97% maternal seroprevalence were screened for cCMVI and HL. cCMVI was confirmed by detection of CMV-DNA in saliva and urine at age <3 weeks.

Results: Overall, 68 (0.6%; 95% confidence interval [CI], 0.4-0.7) neonates were identified with cCMVI. Of the 91 (0.8%) newborns who failed the HS, 24 (26.4%) were confirmed with HL, including 7 (29.2%; 95% CI, 17.2-59.3) with cCMVI. Another newborn with cCMVI passed the HS but was confirmed with HL at age 21 days. Of the 62 neonates with cCMVI who underwent a complete hearing evaluation, 8 (12.9%; 95% CI, 6.7-23.4) had HL and most (7/8; 87.5%; 95% CI, 46.6-99.7) were identified by HS. The rate of CMV-related HL was 8 per 11 887 neonates (0.7 per 1000 live births). The prevalence ratio of HL among neonates with cCMVI compared to CMV-uninfected neonates was 89.5 (95% CI, 39.7-202.0). No late-onset cCMVI-related HL was detected during a median follow-up of 36 months.

Conclusions: cCMVI is an important cause of HL in childhood in all settings. Integrating targeted cCMVI screening among neonates who fail a HS could be a reasonable, cost-effective strategy to identify newborns with early-onset cCMVI-related HL.
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http://dx.doi.org/10.1093/cid/ciz413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931844PMC
March 2020

CD4 T cells are required for maintenance of CD8 T cells and virus control in the brain of MCMV-infected newborn mice.

Med Microbiol Immunol 2019 Aug 28;208(3-4):487-494. Epub 2019 Mar 28.

Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, B. Branchetta 20, 51000, Rijeka, Croatia.

Cytomegalovirus (CMV) infection is a significant public health problem. Congenital CMV infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Immune protection against mouse cytomegalovirus (MCMV) is primarily mediated by NK cells and CD8 T cells, while CD4 T cells are not needed for control of MCMV in majority of organs in immunocompetent adult mice. Here, we set out to determine the role of CD4 T cells upon MCMV infection of newborn mice. We provide evidence that CD4 T cells are essential for clearance of MCMV infection in brain of neonatal mice and for prevention of recurrence of latent MCMV. In addition, we provide evidence that CD4 T cells are required for induction and maintenance of tissue-resident memory CD8 T cells in the brain of mice perinatally infected with MCMV.
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http://dx.doi.org/10.1007/s00430-019-00601-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640853PMC
August 2019

Role of antibodies in confining cytomegalovirus after reactivation from latency: three decades' résumé.

Med Microbiol Immunol 2019 Aug 28;208(3-4):415-429. Epub 2019 Mar 28.

Department of Histology and Embryology and Center for Proteomics, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000, Rijeka, Croatia.

Cytomegaloviruses (CMVs) are highly prevalent herpesviruses, characterized by strict species specificity and the ability to establish non-productive latent infection from which reactivation can occur. Reactivation of latent human CMV (HCMV) represents one of the most important clinical challenges in transplant recipients secondary to the strong immunosuppression. In addition, HCMV is the major viral cause of congenital infection with severe sequelae including brain damage. The accumulated evidence clearly shows that cellular immunity plays a major role in the control of primary CMV infection as well as establishment and maintenance of latency. However, the efficiency of antiviral antibodies in virus control, particularly in prevention of congenital infection and virus reactivation from latency in immunosuppressed hosts, is much less understood. Because of a strict species specificity of HCMV, the role of antibodies in controlling CMV disease has been addressed using murine CMV (MCMV) as a model. Here, we review and discuss the role played by the antiviral antibody response during CMV infections with emphasis on latency and reactivation not only in the MCMV model, but also in relevant clinical settings. We provide evidence to conclude that antiviral antibodies do not prevent the initiating molecular event of virus reactivation from latency but operate by preventing intra-organ spread and inter-organ dissemination of recurrent virus.
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http://dx.doi.org/10.1007/s00430-019-00600-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705608PMC
August 2019

HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission.

Proc Natl Acad Sci U S A 2019 02 7;116(9):3728-3733. Epub 2019 Feb 7.

Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239;

Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients' and pregnant mothers' sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.
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http://dx.doi.org/10.1073/pnas.1814835116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397592PMC
February 2019

New therapies for human cytomegalovirus infections.

Antiviral Res 2018 11 15;159:153-174. Epub 2018 Sep 15.

Department of Pediatrics, University of Alabama School of Medicine, Birmingham AL 35233-1711, USA. Electronic address:

The recent approval of letermovir marks a new era of therapy for human cytomegalovirus (HCMV) infections, particularly for the prevention of HCMV disease in hematopoietic stem cell transplant recipients. For almost 30 years ganciclovir has been the therapy of choice for these infections and by today's standards this drug exhibits only modest antiviral activity that is often insufficient to completely suppress viral replication, and drives the selection of drug-resistant variants that continue to replicate and contribute to disease. While ganciclovir remains the therapy of choice, additional drugs that inhibit novel molecular targets, such as letermovir, will be required as highly effective combination therapies are developed not only for the treatment of immunocompromised hosts, but also for congenitally infected infants. Sustained efforts, largely in the biotech industry and academia, have identified additional highly active lead compounds that have progressed into clinical studies with varying levels of success and at least two have the potential to be approved in the near future. Some of the new drugs in the pipeline inhibit new molecular targets, remain effective against isolates that have developed resistance to existing therapies, and promise to augment existing therapeutic regimens. Here, we will describe some of the unique features of HCMV biology and discuss their effect on therapeutic needs. Existing drugs will also be discussed and some of the more promising candidates will be reviewed with an emphasis on those progressing through clinical studies. The in vitro and in vivo antiviral activity, spectrum of antiviral activity, and mechanism of action of new compounds will be reviewed to provide an update on potential new therapies for HCMV infections that have progressed significantly in recent years.
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http://dx.doi.org/10.1016/j.antiviral.2018.09.003DOI Listing
November 2018

Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection.

Authors:
William J Britt

Viruses 2018 08 3;10(8). Epub 2018 Aug 3.

Departments of Pediatrics, Microbiology, and Neurobiology, University of Alabama School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Congenital human cytomegalovirus (HCMV) is the most common viral infection of the developing fetus, and a significant cause of neurodevelopmental abnormalities in infants and children. Congenital HCMV infections account for an estimated 25% of all cases of hearing loss in the US. It has long been argued that maternal adaptive immune responses to HCMV can modify both the likelihood of intrauterine transmission of HCMV, and the severity of fetal infection and risk of long term sequelae in infected infants. Over the last two decades, multiple studies have challenged this paradigm, including findings that have demonstrated that the vast majority of infants with congenital HCMV infections in most populations are born to women with established immunity prior to conception. Furthermore, the incidence of clinically apparent congenital HCMV infection in infants born to immune and non-immune pregnant women appears to be similar. These findings from natural history studies have important implications for the design, development, and testing of prophylactic vaccines and biologics for this perinatal infection. This brief overview will provide a discussion of existing data from human natural history studies and animal models of congenital HCMV infections that have described the role of maternal immunity in the natural history of this perinatal infection.
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http://dx.doi.org/10.3390/v10080405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116058PMC
August 2018

Cytomegalovirus promotes intestinal macrophage-mediated mucosal inflammation through induction of Smad7.

Mucosal Immunol 2018 11 3;11(6):1694-1704. Epub 2018 Aug 3.

Departments of Medicine (Gastroenterology), University of Alabama, Birmingham, Alabama, 35294, USA.

Intestinal macrophages in healthy human mucosa are profoundly down-regulated for inflammatory responses (inflammation anergy) due to stromal TGF-β inactivation of NF-κB. Paradoxically, in cytomegalovirus (CMV) intestinal inflammatory disease, one of the most common manifestations of opportunistic CMV infection, intestinal macrophages mediate severe mucosal inflammation. Here we investigated the mechanism whereby CMV infection promotes macrophage-mediated mucosal inflammation. CMV infected primary intestinal macrophages but did not replicate in the cells or reverse established inflammation anergy. However, CMV infection of precursor blood monocytes, the source of human intestinal macrophages in adults, prevented stromal TGF-β-induced differentiation of monocytes into inflammation anergic macrophages. Mechanistically, CMV up-regulated monocyte expression of the TGF-β antagonist Smad7, blocking the ability of stromal TGF-β to inactivate NF-κB, thereby enabling MyD88 and NF-κB-dependent cytokine production. Smad7 expression also was markedly elevated in mucosal tissue from subjects with CMV colitis and declined after antiviral ganciclovir therapy. Confirming these findings, transfection of Smad7 antisense oligonucleotide into CMV-infected monocytes restored monocyte susceptibility to stromal TGF-β-induced inflammation anergy. Thus, CMV-infected monocytes that recruit to the mucosa, not resident macrophages, are the source of inflammatory macrophages in CMV mucosal disease and implicate Smad7 as a key regulator of, and potential therapeutic target for, CMV mucosal disease.
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http://dx.doi.org/10.1038/s41385-018-0041-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405939PMC
November 2018

Human Cytomegalovirus Immediate Early 1 Protein Causes Loss of SOX2 from Neural Progenitor Cells by Trapping Unphosphorylated STAT3 in the Nucleus.

J Virol 2018 09 16;92(17). Epub 2018 Aug 16.

State Key Laboratory of Virology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Wuhan Institute of Virology, Wuhan, China

The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV infection to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here, we show that HCMV infection of NPCs results in loss of the SOX2 protein, a key pluripotency-associated transcription factor. SOX2 depletion maps to the HCMV major immediate early (IE) transcription unit and is individually mediated by the IE1 and IE2 proteins. IE1 causes SOX2 downregulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Deranged signaling resulting in depletion of a critical stem cell protein is an unanticipated mechanism by which the viral major IE proteins may contribute to brain development disorders caused by congenital HCMV infection. Human cytomegalovirus (HCMV) infections are a leading cause of brain damage, hearing loss, and other neurological disabilities in children. We report that the HCMV proteins known as IE1 and IE2 target expression of human SOX2, a central pluripotency-associated transcription factor that governs neural progenitor cell (NPC) fate and is required for normal brain development. Both during HCMV infection and when expressed alone, IE1 causes the loss of SOX2 from NPCs. IE1 mediates SOX2 depletion by targeting STAT3, a critical upstream regulator of SOX2 expression. Our findings reveal an unanticipated mechanism by which a common virus may cause damage to the developing nervous system and suggest novel targets for medical intervention.
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http://dx.doi.org/10.1128/JVI.00340-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096794PMC
September 2018

Seroconversion for Cytomegalovirus Infection During Pregnancy and Fetal Infection in a Highly Seropositive Population: "The BraCHS Study".

J Infect Dis 2018 09;218(8):1200-1204

Department of Pediatrics, The University of Alabama at Birmingham.

We determined the risk of seroconversion in seronegative pregnant women living in a high seroprevalence population. Cytomegalovirus (CMV)-immunoglobulin G reactivity was determined at the 1st trimester in all women and sequentially for seronegative women. A total of 1915 of 1952 (98.1%; 95% confidence interval [CI], 97.4%-98.7%) women were seropositive, and 36 (1.8%; 95% CI, 1.3%-2.6%) were seronegative. Five of the 36-seronegative women seroconverted for a cumulative rate of 13.9% (95% CI, 4.8%-30.6%). Congenital CMV infection was diagnosed in 1 of 36 infants (2.8%; 95% CI, 0.5%-63.9%) born to seronegative women compared with 8 of 1685 (0.5%; 95% CI, 0.2%-1.0%) infants born to seropositive mothers. Even with a high risk of primary infection in seronegative women, most CMV-infected infants were born to women with pre-existing seroimmunity.
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http://dx.doi.org/10.1093/infdis/jiy321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129109PMC
September 2018

Adverse outcomes of pregnancy-associated Zika virus infection.

Authors:
William J Britt

Semin Perinatol 2018 04 6;42(3):155-167. Epub 2018 Mar 6.

Department of Pediatrics, University of Alabama School of Medicine, Childrens Hospital Harbor Bldg 160, Birmingham, AL 35233. Electronic address:

The spread of Zika virus to the Americas was accompanied by surge in the number of infants with CNS abnormalities leading to a declaration of a health emergency by the WHO. This was accompanied by significant responses from governmental health agencies in the United States and Europe that resulted in significant new information described in the natural history of this perinatal infection in a very short period of time. Although much has been learned about Zika virus infection during pregnancy, limitations of current diagnostics and the challenges for accurate serologic diagnosis of acute Zika virus infection has restricted our understanding of the natural history of this perinatal infection to infants born to women with clinical disease during pregnancy and to Zika exposed infants with obvious clinical stigmata of disease. Thus, the spectrum of disease in infants exposed to Zika virus during pregnancy remains to be defined. In contrast, observations in informative animal models of Zika virus infections have provided rational pathways for vaccine development and existing antiviral drug development programs for other flaviviruses have resulted in accelerated development for potential antiviral therapies. This brief review will highlight some of the current concepts of the natural history of Zika virus during pregnancy.
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http://dx.doi.org/10.1053/j.semperi.2018.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442220PMC
April 2018

Brain-resident memory CD8 T cells induced by congenital CMV infection prevent brain pathology and virus reactivation.

Eur J Immunol 2018 06 23;48(6):950-964. Epub 2018 Mar 23.

Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.

Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with mouse cytomegalovirus (MCMV) intraperitoneally is a well-established model of congenital human cytomegalovirus infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here, we used this model to investigate the role, dynamics, and phenotype of CD8 T cells in the brain following infection of newborn mice. We show that CD8 T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T cells) that persist for lifetime. Adoptively transferred virus-specific CD8 T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology, and remain in the brain as T cells. Brain CD8 T cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8 T cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.
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http://dx.doi.org/10.1002/eji.201847526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422351PMC
June 2018

Cytomegalovirus Shedding in Seropositive Pregnant Women From a High-Seroprevalence Population: The Brazilian Cytomegalovirus Hearing and Maternal Secondary Infection Study.

Clin Infect Dis 2018 08;67(5):743-750

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Brazil.

Background: Most congenital cytomegalovirus (CMV) infections in highly seropositive populations occur in infants born to women with preexisting CMV seroimmunity. Although essential for developing prevention strategies, CMV shedding patterns in pregnant women with nonprimary infections have not been characterized. We investigated correlates of CMV shedding in a cohort of seropositive pregnant women.

Methods: In a prospective study, saliva, urine, vaginal swabs, and blood were collected from 120 CMV-seropositive women in the first, second, and third trimesters and 1 month postpartum. Specimens were tested for CMV DNA by polymerase chain reaction. We analyzed the contribution of the specific maternal characteristics to viral shedding.

Results: CMV shedding was detected at least once in 42 (35%) women. Mothers living with or providing daily care to young children (3-6 years) were twice as likely to shed CMV at least once compared to women with less exposure to young children (58% vs 26%; adjusted relative risk [aRR], 2.21; 95% confidence interval [CI], 1.37-3.56). Living in crowded households (≥2 people per room) was associated with viral shedding (64% vs 31%; aRR, 1.99; 95% CI, 1.26-3.13). Sexual activity as indicated by the number of sexual partners per year or condom use was not found to be a correlate of viral shedding.

Conclusions: CMV shedding is relatively frequent in seropositive pregnant women. The association between virus shedding and caring for young children as well as crowded living conditions may provide opportunities for increased exposures that could lead to CMV reinfections in seropositive women.
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http://dx.doi.org/10.1093/cid/ciy166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094000PMC
August 2018

WDR5 Facilitates Human Cytomegalovirus Replication by Promoting Capsid Nuclear Egress.

J Virol 2018 05 13;92(9). Epub 2018 Apr 13.

State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology, Wuhan Institute of Virology, Wuhan, China

WD repeat-containing protein 5 (WDR5) is essential for assembling the VISA-associated complex to induce a type I interferon antiviral response to Sendai virus infection. However, the roles of WDR5 in DNA virus infections are not well described. Here, we report that human cytomegalovirus exploits WDR5 to facilitate capsid nuclear egress. Overexpression of WDR5 in fibroblasts slightly enhanced the infectious virus yield. However, WDR5 knockdown dramatically reduced infectious virus titers with only a small decrease in viral genome replication or gene expression. Further investigation of late steps of viral replication found that WDR5 knockdown significantly impaired formation of the viral nuclear egress complex and induced substantially fewer infoldings of the inner nuclear membrane. In addition, fewer capsids were associated with these infoldings, and there were fewer capsids in the cytoplasm. Restoration of WDR5 partially reversed these effects. These results suggest that WDR5 knockdown impairs the nuclear egress of capsids, which in turn decreases virus titers. These findings reveal an important role for a host factor whose function(s) is usurped by a viral pathogen to promote efficient replication. Thus, WDR5 represents an interesting regulatory mechanism and a potential antiviral target. Human cytomegalovirus (HCMV) has a large (∼235-kb) genome with over 170 open reading frames and exploits numerous cellular factors to facilitate its replication. HCMV infection increases protein levels of WD repeat-containing protein 5 (WDR5) during infection, overexpression of WDR5 enhances viral replication, and knockdown of WDR5 dramatically attenuates viral replication. Our results indicate that WDR5 promotes the nuclear egress of viral capsids, the depletion of WDR5 resulting in a significant decrease in production of infectious virions. This is the first report that WDR5 favors HCMV, a DNA virus, replication and highlights a novel target for antiviral therapy.
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http://dx.doi.org/10.1128/JVI.00207-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899187PMC
May 2018

Human Cytomegalovirus Nuclear Capsids Associate with the Core Nuclear Egress Complex and the Viral Protein Kinase pUL97.

Viruses 2018 01 13;10(1). Epub 2018 Jan 13.

Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen 91054, Germany.

The nuclear phase of herpesvirus replication is regulated through the formation of regulatory multi-component protein complexes. Viral genomic replication is followed by nuclear capsid assembly, DNA encapsidation and nuclear egress. The latter has been studied intensely pointing to the formation of a viral core nuclear egress complex (NEC) that recruits a multimeric assembly of viral and cellular factors for the reorganization of the nuclear envelope. To date, the mechanism of the association of human cytomegalovirus (HCMV) capsids with the NEC, which in turn initiates the specific steps of nuclear capsid budding, remains undefined. Here, we provide electron microscopy-based data demonstrating the association of both nuclear capsids and NEC proteins at nuclear lamina budding sites. Specifically, immunogold labelling of the core NEC constituent pUL53 and NEC-associated viral kinase pUL97 suggested an intranuclear NEC-capsid interaction. Staining patterns with phospho-specific lamin A/C antibodies are compatible with earlier postulates of targeted capsid egress at lamina-depleted areas. Important data were provided by co-immunoprecipitation and in vitro kinase analyses using lysates from HCMV-infected cells, nuclear fractions, or infectious virions. Data strongly suggest that nuclear capsids interact with pUL53 and pUL97. Combined, the findings support a refined concept of HCMV nuclear trafficking and NEC-capsid interaction.
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http://dx.doi.org/10.3390/v10010035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795448PMC
January 2018

Immune responses to congenital cytomegalovirus infection.

Microbes Infect 2018 Oct - Nov;20(9-10):543-551. Epub 2017 Dec 26.

Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia; Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia. Electronic address:

Human cytomegalovirus (HCMV) is the most common cause of viral infection acquired in utero. Even though the infection has been studied for several decades, immune determinants important for virus control and mechanisms of long-term sequelae caused by infection are still insufficiently characterized. Animal models of congenital HCMV infection provide unique opportunity to study various aspects of human disease. In this review, we summarize current knowledge on the role of immune system in congenital CMV infection, with emphasis on lessons learned from mouse model of congenital CMV infection.
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http://dx.doi.org/10.1016/j.micinf.2017.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019571PMC
September 2019

Herpesviridae Infection: Prevention, Screening, and Management.

Clin Obstet Gynecol 2018 03;61(1):157-176

Pediatric Division of Infectious Diseases, the University of Alabama at Birmingham, Birmingham, Alabama.

Bacterial, viral, and parasitic pathogens add significant morbidity and even mortality to pregnancy-with adverse effects extending to both the gravida and the newborn. Three herpesviruses deserve considerable attention given the effects of perinatal infection on obstetric outcomes, specifically maternal and neonatal morbidity. In the following review, we will provide a description of cytomegalovirus, herpes simplex virus, and varicella zoster virus. For each viral pathogen, we will describe the epidemiology, natural history, screening and diagnosis modalities, treatments, and implications for antepartum care. Furthermore, we will highlight future directions of work in reducing the morbidities associated with these viral pathogens.
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http://dx.doi.org/10.1097/GRF.0000000000000335DOI Listing
March 2018

Pathogenesis of Non-Zika Congenital Viral Infections.

J Infect Dis 2017 12;216(suppl_10):S912-S918

Division of Pediatric Infectious Diseases, University of Alabama at Birmingham.

A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 from South and Central America and the Caribbean. Although the full spectrum of ZIKV infection of the newborn has yet to be determined, other maternal viral infections resulting in transmission to the fetus provide instructive lessons that can be applied to the prospective evaluation of individuals with ZIKV infection. This review focuses on those other congenital infections, including rubella, congenital cytomegalovirus, human immunodeficiency virus, hepatitis B virus, and neonatal herpes simplex virus, from which lessons for the evaluation of ZIKV in the newborn can be applied.
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http://dx.doi.org/10.1093/infdis/jix431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853682PMC
December 2017

Protective capacity of neutralizing and non-neutralizing antibodies against glycoprotein B of cytomegalovirus.

PLoS Pathog 2017 Aug 30;13(8):e1006601. Epub 2017 Aug 30.

Virologisches Institut, Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

Human cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infected in utero. Antiviral chemotherapy remains problematic due to toxicity of the available compounds and the emergence of viruses resistant to available antiviral therapies. Antiviral antibodies could represent a valuable alternative strategy to limit the clinical consequences of viral disease in patients. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus neutralizing antibodies. However, the role of anti-gB antibodies in the course of the infection in-vivo remains unknown. We have used a murine CMV (MCMV) model to generate and study a number of anti-gB monoclonal antibodies (mAbs) with differing virus-neutralizing capacities. The mAbs were found to bind to similar antigenic structures on MCMV gB that are represented in HCMV gB. When mAbs were used in immunodeficient RAG-/- hosts to limit an ongoing infection we observed a reduction in viral load both with mAbs having potent neutralizing capacity in-vitro as well as mAbs classified as non-neutralizing. In a therapeutic setting, neutralizing mAbs showed a greater capacity to reduce the viral burden compared to non-neutralizing antibodies. Efficacy was correlated with sustained concentration of virus neutralizing mAbs in-vivo rather than their in-vitro neutralizing capacity. Combinations of neutralizing mAbs further augmented the antiviral effect and were found to be as potent in protection as polyvalent serum from immune animals. Prophylactic administration of mAbs before infection was also protective and both neutralizing and non-neutralizing mAbs were equally effective in preventing lethal infection of immunodeficient mice. In summary, our data argue that therapeutic application of potently neutralizing mAbs against gB represent a strategy to modify the outcome of CMV infection in immunodeficient hosts. When present before infection, both neutralizing and non-neutralizing anti-gB exhibited protective capacity.
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http://dx.doi.org/10.1371/journal.ppat.1006601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595347PMC
August 2017