Abstract
Congenital human cytomegalovirus (HCMV) infection is the major cause of birth defects and a precise definition of the HCMV-specific T-cell response in primary infection may help define reliable correlates of immune protection during pregnancy. In this study, a high throughput method was used to define the frequency of CD4+ and CD8+ T cells specific for four HCMV proteins in the naïve compartment of seronegative subjects and the effector/memory compartments of subjects with primary/remote HCMV infection. The naïve repertoire displayed comparable frequencies of T cells that were reactive with HCMV structural (pp65, gB and the pentamer gHgLpUL128L) and non-structural (IE-1) proteins. Whereas, following natural infection, the majority of effector/memory CD4+ and CD8+ T cells recognized either gB or IE-1, respectively, and pp65. The pattern of T cell reactivity was comparable at early and late stages of infection and in pregnant women with primary HCMV infection transmitting or not transmitting the virus to the fetus. At an early stage of primary infection, about 50% of HCMV-reactive CD4+ T cells were long-term IL-7Rpos memory cells, while 6–12 months later, the frequency of these cells increased to 70%, approaching 100% in remote infections. In contrast, only 10–20% of HCMV-specific CD8+ T cells were long-term memory cells up to 12 months after infection onset, thereafter increasing to 70% in remote infections. Interestingly, a significantly higher frequency of HCMV-specific CD4+ T cells with a long-term IL-7Rpos memory phenotype was observed in non-transmitting compared to transmitting women. These findings indicate that immunodominance in HCMV infection is not predetermined in the naïve compartment, but is the result of virus-host interactions and suggest that prompt control of HCMV infection in pregnancy is associated with the rapid development of long-term IL-7Rpos memory HCMV-specific CD4+ T cells and a low risk of virus transmission to the fetus.
Highlights
Human cytomegalovirus (HCMV) is the most common cause of congenital infection, and may lead to mental retardation, psychomotor delay, hearing loss, speech and language disabilities, behavioral disorders and visual impairment
We provided evidence that delayed T and B cell responses to HCMV primary infection in pregnancy are associated with virus transmission to the fetus [7,8,9,10,11,12]
We extended the analysis of the development of T-cell responses to HCMV and their relationship with congenital HCMV infection after primary infection in pregnancy
Summary
Human cytomegalovirus (HCMV) is the most common cause of congenital infection, and may lead to mental retardation, psychomotor delay, hearing loss, speech and language disabilities, behavioral disorders and visual impairment. Vertical transmission occurs in about 0.6% of pregnancies [1], and the infected fetus may present with symptoms at birth or develop severe long-term sequelae (in about 20% of cases) [2, 3]. We provided evidence that delayed T and B cell responses to HCMV primary infection in pregnancy are associated with virus transmission to the fetus [7,8,9,10,11,12]. We used a high throughput cell-based screening assay [13] to measure, with high sensitivity, the frequencies of HCMV-specific T cells in naïve and effector/memory subsets of HCMV seronegative and seropositive donors and patients following primary HCMV infection, including pregnant women transmitting (T) or non-transmitting (NT) the virus to the fetus
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