These observations indicate that initiation of maternal ART before pregnancy reduces the susceptibility of HEU infants born in a HIC to severe infections and that this effect could be related to the prevention of immune alterations during fetal life.

Human CMV establishes lifelong persistence after primary infection. Chronic CMV infection is associated with intermittent viral reactivation inducing high frequencies of CD4+ T lymphocytes with potent antiviral and helper properties. Primary CMV infection is characterized by an intense viral replication lasting for several months. The impact of this prolonged exposure to high Ag loads on the functionality of CD4+ T cells remains incompletely understood. In pregnant women with primary CMV infection, we observed that CMV-specific CD4+ T lymphocytes had a decreased capacity to proliferate and to produce IL-2. A very large proportion of CMV-specific CD4+ T cells had downregulated the expression of CD28, a costimulatory molecule centrally involved in the production of IL-2. Unexpectedly, both CD28− and CD28+CD4+ T cells produced low levels of IL-2. This defective production of IL-2 was part of a larger downregulation of cytokine production. Indeed, CMV-specific CD4+ T cells produced lower amounts of IFN-γ and TNF-α and showed lower functional avidity during primary as compared with chronic infection. Increased programmed death-1 expression was observed in CD28+ CMV-specific CD4+ T cells, and programmed death-1 inhibition increased proliferative responses. These results indicate that primary CMV infection is associated with the exhaustion of CMV-specific CD4+ T cells displaying low functional avidity for viral Ags.

Functional exhaustion limits effector CD4(+) and CD8(+) T-lymphocyte responses to CMV during fetal life.

Following congenital human CMV (HCMV) infection, 15-20% of infected newborns develop severe health problems whereas infection in immunocompetent adults rarely causes illness. The immaturity of neonatal antigen presenting cells could play a pivotal role in this susceptibility. Neonatal myeloid DC were shown to be deficient in IFN-b and IL-12 synthesis in response to TLR triggering. We studied the response of cord and adult bloodderived myeloid DC to HCMV infection. Neonatal and adult DC were equally susceptible to in vitro HCMV infection. Among immunomodulatory cytokines, IL-12, IFN-b and IFN-k1 were produced at lower levels by neonatal as compared with adult DC. In contrast, neonatal and adult DC produced similar levels of IFN-a and IFN-inducible genes. Microarray analysis indicated that among the more than thousand genes up-or down-regulated by HCMV infection of myeloid DC, 88 were differently regulated between adult and neonatal DC. We conclude that neonatal and adult DC trigger a partly different response to HCMV infection. The deficient IL-12 and mature IFN-a production by neonatal DC exposed to HCMV are likely to influence the quality of the T lymphocyte response to HCMV infection in early life.

Primary CMV infection mobilizes a large pool of memory B cells that includes activated and atypical MBCs. The functional regulation of CMV-specific MBCs may limit the production of antibodies and the control of viral dissemination.