Maternal LAMP/p55gagHIV-1 DNA Immunization Induces In Utero Priming and a Long-Lasting Immune Response in Vaccinated Neonates

Paula Ordonhez Rigato,Joseph Thomas August,Orlando Guerra Piubelli,Ernesto Torres Marques,Noemia Mie Orii,Adriana Letícia Goldoni,Milton Maciel,Maria Notomi Sato,Alberto José Da Silva Duarte,Paul A Goepfert

doi:10.1371/journal.pone.0031608

Paula Ordonhez Rigato, Joseph Thomas August + Show 8 more

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https://doi.org/10.1371/journal.pone.0031608

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Abstract

Infants born to HIV-infected mothers are at high risk of becoming infected during gestation or the breastfeeding period. A search is thus warranted for vaccine formulations that will prevent mother-to-child HIV transmission. The LAMP/gag DNA chimeric vaccine encodes the HIV-1 p55gag fused to the lysosome-associated membrane protein-1 (LAMP-1) and has been shown to enhance anti-Gag antibody (Ab) and cellular immune responses in adult and neonatal mice; such a vaccine represents a new concept in antigen presentation. In this study, we evaluated the effect of LAMP/gag DNA immunization on neonates either before conception or during pregnancy. LAMP/gag immunization of BALB/c mice before conception by the intradermal route led to the transfer of anti-Gag IgG1 Ab through the placenta and via breastfeeding. Furthermore, there were an increased percentage of CD4+CD25+Foxp3+T cells in the spleens of neonates. When offspring were immunized with LAMP/gag DNA, the anti-Gag Ab response and the Gag-specific IFN-γ-secreting cells were decreased. Inhibition of anti-Gag Ab production and cellular responses were not observed six months after immunization, indicating that maternal immunization did not interfere with the long-lasting memory response in offspring. Injection of purified IgG in conjunction with LAMP/gag DNA immunization decreased humoral and cytotoxic T-cell responses. LAMP/gag DNA immunization by intradermal injection prior to conception promoted the transfer of Ab, leading to a diminished response to Gag without interfering with the development of anti-Gag T- and B-cell memory. Finally, we assessed responses after one intravenous injection of LAMP/gag DNA during the last five days of pregnancy. The intravenous injection led to in utero immunization. In conclusion, DNA vaccine enconding LAMP-1 with Gag and other HIV-1 antigens should be considered in the development of a protective vaccine for the maternal/fetal and newborn periods.

Highlights

Despite the use of antiretroviral regimens to prevent intrapartum and breast milk HIV transmission [1], mother-to-child transmission (MTCT) of HIV-1 is still the major route of pediatric infection [2]
We evaluated the effect of the LAMP/gag DNA vaccine which was administered to mice either before or during pregnancy on the neonatal immune response
The results showed that one intravenous injection with 100 mg of LAMP/gag or gag DNA during pregnancy was able to prime mothers as determined by the induction of IFN-c spotforming cells (SFCs) that were generated against the immunodominant MHC class I and II epitopes and the p24 protein (Fig. 7A)

Summary

Introduction

Despite the use of antiretroviral regimens to prevent intrapartum and breast milk HIV transmission [1], mother-to-child transmission (MTCT) of HIV-1 is still the major route of pediatric infection [2]. Vertical transmission of HIV-1 depends on the maternal HIV-1 viral load, infant exposure to infected fluids upon delivery and breastfeeding, and the duration and regimen of antiretroviral treatment [3,4]. Vaccines that are administered to HIV-1-infected women during the neonatal period or pregnancy and that are able to induce high levels of neutralizing Ab with long-lasting effects are strong candidates for avoiding MTCT. Studying immunologic interventions, such as maternal and infant vaccine regimens, that would reduce pre- and postnatal HIV transmission remain crucial for protection against HIV infection

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