HCMV Infection of Human Trophoblast Progenitor Cells of the Placenta Is Neutralized by a Human Monoclonal Antibody to Glycoprotein B and Not by Antibodies to the Pentamer Complex

Zydek, Martin; Petitt, Matthew; Fang-Hoover, June; Adler, Barbara; Kauvar, Lawrence M.; Pereira, Lenore; Tabata, Takako

doi:10.3390/v6031346

Cited by 61 publications

(75 citation statements)

References 75 publications

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“…36,37 Viral titers were adjusted to give a total of 600 to 800 IE1-positive cells/well in 24-well plates. Human MAbs to the pentamer component UL130/131A (TLR310, 1F11) and gB (TRL345), hyperimmune globulin (Cytotect), and negative control MAb Synagis were gifts from Trellis Bioscience (Menlo Park, CA).…”

Section: Virus Neutralization Assaysmentioning

confidence: 99%

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tabata

Petitt

Fang-Hoover

et al. 2016

The American Journal of Pathology

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Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from midgestation placentas formed foci of infection, and interferon-b production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-x L by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-x L , indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment. (Am J Pathol 2016 http://dx

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Section: Virus Neutralization Assaysmentioning

confidence: 99%

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Tabata

Petitt

Fang-Hoover

et al. 2016

The American Journal of Pathology

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“…Our studies of HCMV infection in the human placenta revealed important differences in infection between cell types [15][16][17][18][19] and maternal immune status 7,8,16,20 . Studies of primary human placental cells and tissue models have identified molecular pathways that impair trophoblast differentiation [17][18][19][21][22][23][24] .…”

Section: Under the Microscopementioning

confidence: 90%

“…Studies of primary human placental cells and tissue models have identified molecular pathways that impair trophoblast differentiation [17][18][19][21][22][23][24] . Patterns of viral proteins in infected placentas suggest modulation of infection in early Since the attenuated and clinical strains exhibited markedly distinct levels of infection in placental explants, the differences were quantified by counting the number of cytotrophoblasts expressing IE1…”

Section: Under the Microscopementioning

confidence: 99%

Cytomegalovirus infection and pathogenesis in the human placenta

2015

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As shown in Figure 1, the human placenta is composed of chorionic villi bathed in maternal blood and villi that anchor the placenta in the uterine wall (decidua), attaching the fetus to the mother (panel a1). The individual chorionic villus contains a connective core with blood vessels that carry substances to the fetal circulation (panel a2). Placentation is a stepwise process whereby villus cytotrophoblasts (vCTB) attached to the basement membrane as a polarised epithelium leave the membrane to differentiate along one of two independent pathways depending on their location. In floating villi, they fuse to form a multinucleate synctiotrophoblast (STB) covering attached at one end to the tree-like fetal portion of the placenta. The rest of the villus floats in a stream of maternal blood, which optimises exchange of substances between the maternal and fetal circulation. In the pathway that gives rise to anchoring villi, cytotrophoblasts aggregate into cell columns of non-polarised mononuclear cells that attach to and then invade the uterine wall (iCTBs).

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“…Furthermore, human B cells have been shown to perform limited VDJ recombination events that are required for antibodies that target AD-2 [53], whereas there are numerous possibilities for generation of AD-1-specific antibodies. Interestingly, antibodies to AD-2 have been demonstrated to block placental infection of HCMV [54] and may, therefore, be the most critical site for antibodies to target to reduce vertical transmission. The AD-4 and AD-5 regions have been identified and mapped much more recently by isolating human B cells with affinity for recombinant gB [49].…”

Section: Immune Response To Hcmv Gbmentioning

confidence: 99%

Human Cytomegalovirus Vaccination: Progress and Perspectives of Recombinant gB

Manghera

McLean

2016

Future Virol.

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A vaccine for Human cytomegalovirus (HCMV) remains a high priority as complications following infection are observed in immunocompromised individuals and in congenitally infected neonates. Numerous preclinical and clinical studies have investigated vaccine strategies ranging from live attenuated preparations, nucleic acid-based approaches and recombinant delivery systems to subunit vaccines. These have defined the importance of both cell-mediated and humoral immunity to viral gB in the control of HCMV infection. This review will cover clinical trials investigating vaccine approaches that have incorporated gB and discuss the future perspectives of the recombinant gB subunit vaccine for HCMV. BackgroundHuman cytomegalovirus (HCMV) is a ubiquitous pathogen, known to infect all human populations worldwide [1]. It is an enveloped dsDNA virus that is the largest member of the Herpesviridae family that also includes important pathogens, such as HSV-1 and HSV-2, EBV and varicella zoster virus (VZV), all of which are widespread in human populations [2]. The HCMV genome is approximately 230 kbp encoding 200-250 open reading frames, many of which facilitate immune evasion [3]. A recent study of the HCMV genome and translation products has suggested that it may be even more complex than anticipated with regulation of alternate transcripts allowing for numerous polypeptides to be expressed [4]. Transmission of HCMV predominantly occurs via body fluids, such as saliva, blood, urine and breast milk, leading to contact of the mucosal surfaces, primarily infecting epithelial and endothelial cells, followed by dissemination to numerous organs and tissues [5]. HCMV is, therefore, able to infect a wide range of cells including endothelial cells, epithelial cells, fibroblasts, smooth muscle cells, leukocytes and dendritic cells [5,6]. Similarly to other Herpesviridae family members, HCMV is capable of both lytic and latent infections [7], but primary infection and reactivation from latency are often asymptomatic in immunocompetent individuals [8]. HCMV infection and reactivation in both solid organ and hematopoietic stem cell transplant recipients, and fetal exposure in utero poses a major threat. Immunocompromised individuals, including AIDS patients [9,10] and transplant patients [11,12], are at increased risk of both reactivation or reinfection, and primary HCMV infection has serious consequences for the developing fetus in pregnant women [8]. It is estimated that HCMV congenital infection occurs in 0.5-2% of all annual pregnancies [13], and approximately 10% of infants with congenital HCMV infection present with clinical manifestations at birth, such as hearing loss and neurological developmental defects [14]. Additionally, late-onset hearing disorders can occur with both symptomatic and asymptomatic congenital infection, which [17], which may also be effective in treating congenital infections [18]. Based on the widespread prevalence of HCMV, limited treatment options and the potential for significant morbidity, an effective ...

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HCMV Infection of Human Trophoblast Progenitor Cells of the Placenta Is Neutralized by a Human Monoclonal Antibody to Glycoprotein B and Not by Antibodies to the Pentamer Complex

Cited by 61 publications

References 75 publications

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Cytomegalovirus infection and pathogenesis in the human placenta

Human Cytomegalovirus Vaccination: Progress and Perspectives of Recombinant gB

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