Fetal Human Cytomegalovirus Transmission Correlates with Delayed Maternal Antibodies to gH/gL/pUL128-130-131 Complex during Primary Infection

Abstract

Primary human cytomegalovirus (HCMV) infections during pregnancy are associated with a high risk of virus transmission to the fetus. To identify correlates of intrauterine HCMV transmission, serial serum samples from HCMV transmitter and non-transmitter pregnant women with primary HCMV infection were analyzed for the presence of neutralizing antibodies against different glycoproteins and glycoprotein complexes, which are known to mediate entry into distinct types of host cells. Neutralizing activity was detected in the sera early after primary infection; absorption with a soluble pentameric complex formed by gH/gL/pUL128-131, but not with gH/gL dimer or with gB, abolished the capacity of sera to neutralize infection of epithelial cells. Importantly, an early, high antibody response to pentamer antigenic sites was associated with a significantly reduced risk of HCMV transmission to the fetus. This association is consistent with the high in vitro inhibition of HCMV infection of epithelial/endothelial cells as well as cell-to-cell spreading and virus transfer to leukocytes by anti-pentamer antibodies. Taken together, these findings indicate that the HCMV pentamer complex is a major target of the antibody-mediated maternal immunity.

A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus

“…Previous data showed that neutralizing antibodies, as measured in endothelial or epithelial cells with the use of the VR1814 CMV prototype, are directed primarily against the pentameric gH/gL/pUL128L complex 17,18 and represent the major neutralizing component of human serum and commercial hyperimmune globulin. 19,20 As confirmed in this study, these neutralizing antibodies are produced and peak very early after the onset of primary infection, without a clear difference between mothers who transmit the virus and mothers who do not. 12,21 On the other hand, neutralizing antibodies against AD169 are slower to develop, 12,21,22 and in our study, administration of hyperimmune globulin did not significantly modify their levels.…”

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

“…Total IgG binding responses to either a fibroblast or epithelial-tropic CMV strain did not predict transmission risk. Similar to previous findings in primary maternal CMV infection, the maternal fibroblast neutralizing response also did not predict cCMV transmission [33]. Last, we assessed the binding specificity of maternal IgG antibodies to the CMV glycoproteins gH/gL, gH/gL/gO, and gB and defined neutralizing epitopes of CMV gB and gH.…”

“…We report no association between maternal IgG avidity and risk of CMV transmission among HIV-infected women, yet all had high IgG avidity (RAI range, 0.63-1.00), as expected in a cohort of women with chronic CMV infection. More recently, work by Lilleri et al showed that CMV-nontransmitting women with primary infection had a more rapid appearance of IgG against gH/gL and the pentamer than CMV-transmitting women [33]. In our study, both CMV-transmitting and nontransmitting women had preexisting CMV-specific IgG responses, yet we were able to determine whether the magnitude of pentamerspecific IgG was associated with transmission risk.…”

“…The goal of this case-control study was to determine whether specific humoral immune responses in mothers with chronic HIV/CMV coinfection were predictive of the risk of cCMV transmission. In previous work, both maternal CMV-specific IgG antibody avidity and epithelial cell neutralization potency have been correlated with the risk of cCMV transmission among women with primary CMV infections [22,32,33]. Thus, these responses were considered primary immune predictors of cCMV transmission in a multivariable conditional logistic regression model (Figure 2).…”

Differential kinetics of human cytomegalovirus load and antibody responses in primary infection of the immunocompetent and immunocompromised host

“…In the last few years, significant progress has been made in the diagnosis of human cytomegalovirus (HCMV) infections both for viral DNA quantification by real-time PCR (recently standardized with reference to the WHO International Standard; Furione et al, 2012), and antibody response determination to the HCMV envelope glycoprotein complexes gH/gL/pUL128L (the pentameric complex), gH/gL and gB as well as neutralizing antibodies (Genini et al, 2011;Lilleri et al, 2012Lilleri et al, , 2013.…”