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

Abstract

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.

Keywords: CMV infection in pregnancy; congenital CMV infection; maternal non-primary infection; recurrent infection.

Figure 1.

Increased rate of intrauterine transmission of human cytomegalovirus (HCMV) in seroimmune women with seroconversion to new antigenic variants. Sequential serum samples from women who transmitted virus to their fetuses (transmitters) and matched controls who did not transmit virus (nontransmitters) from a highly HCMV-seroimmune population were assayed for polymorphic antigenic determinants on glycoprotein B and glycoprotein H to determine reinfection with new HCMV variants during pregnancy. ^aApproximately 4000 women were enrolled in this prospective study of HCMV infection during pregnancy. Demographic features of the population including number (median age at enrollment), HCMV seroreactivity, number of sexual partners, and exposure to children <3 years of age are shown. ^bThe rate of seroconversion to a new antigenic variant of HCMV is shown (22.5% in transmitters and 5% in nontransmitters). Note that exposure to children <3 years of age was associated with seroconversion to a new variant of HCMV. Adapted from Yamamoto et al [35].

Figure 2.

Seroconversion to new glycoprotein N (gN) genotype. Congenic human cytomegalovirus (HCMV) was derived from the HB-5 HCMV BAC clone with replacement of UL73 with UL73 encoding gN genotypes 1–4 (Burkhardt, 2009) [56]. These viruses differed only in the amino acid sequence encoded by UL73 (gN). These viruses were used in a microneutralization assay to define neutralizing activity of sequential sera from an immunocompetent woman during the intrapartum period. This is unit of virus neutralizing activity the reciprocal of the serum dilution resulting in 50% reduction in infectivity is shown. Note the increase in neutralizing capacity of sera from the later date for AD169 gN2 indicating the development of new antibody reactivity for this gN genotype.