Impact of the Placental Cytokine-Chemokine Balance on Regulation of Cell-Cell Contact-Induced Human Immunodeficiency Virus Type 1 Translocation across a Trophoblastic Barrier In Vitro

In all human immunodeficiency virus type 1 (HIV-1)-infected women with no preventive antiretroviral therapy during pregnancy, trophoblasts that constitute the first layer of the placental barrier in direct contact with the maternal blood contain viral sequences (23). Nevertheless, more than 90% of the children born from these women are protected against HIV-1 during pregnancy (16, 20), indicating that HIV-1 infection and spread through the placenta are tightly controlled. To determine whether the trophoblastic barrier contributes in limiting in utero transmission of HIV-1, we have developed a model of trophoblastic barrier through which cell-free HIV-1 does not pass (15). In this model, human trophoblast-derived BeWo cells form a tight and polarized cellular barrier. Polarized cells are not productively infected by HIV-1, unless HIV-1-infected (HIV-1+) peripheral blood mononuclear cells (PBMCs) are inoculated onto the apical pole, as described for nonpolarized trophoblasts (1, 8). Even in this case, a translocation of selected maternal HIV-1 quasispecies is observed across the trophoblastic barrier (15). Additional levels of control have to take place at the materno-fetal interface to efficiently limit the transmission of HIV through the trophoblastic barrier and spread to underlying placental cells. Hence, several mechanisms have been proposed to explain the protection of the fetus against maternal HIV during pregnancy. Maternal antibodies (28) and CD4+ T lymphocytes (11, 18) might contribute in limiting in utero transmission of HIV-1. Placental cells secrete a vast array of soluble factors, including growth factors, soluble receptors, and major histocompatibility complex (MHC) class I molecules, such as soluble HLA-G, cytokines, chemokines, and hormones, as well as factors that have not been identified yet (4, 22). These soluble factors most likely exert a concerted activity to create a suppressive environment at the materno-fetal interface, allowing the embryo's semiallogenic tissues to be tolerated by the mother's immune system (22) and the fetus to develop properly. Among these factors, chemokines and cytokines with a known potent anti-HIV-1 activity are detected (4, 6, 9, 24, 26, 27). However, cytokines, such as inflammatory cytokines, the activity of which facilitates HIV infection and replication in different cell types, are also expressed during the various phases of pregnancy. Indirect evidence indicates that, indeed, placental cytokines and chemokines may influence HIV replication in placental cells, particularly in trophoblasts. In women in whom viral load is controlled with antiretroviral therapy, trophoblasts bear no detectable level of HIV sequences but express less inflammatory cytokine and chemokine mRNAs than trophoblasts isolated from placentae of HIV-1-negative women (24). In contrast, expression of inflammatory cytokines is elevated in trophoblasts with a high level of HIV transcripts (18). Along with these findings, interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) were found to stimulate the transcriptional activity of HIV long terminal repeats expressed transiently in isolated trophoblast cells (33) or in trophoblastic cell lines infected with HIV-1 particles pseudotyped with HIV-1 envelope glycoproteins (32), whereas alpha interferon (IFN-α) and IFN-β suppress the transcription driven from the viral promoter (33). Moreover, a correlation between in utero transmission of HIV-1 and expression of Th2 cytokines (IL-4 and IL-10) and leukemia inhibitory factor (LIF) has been reported (3, 26). However, whether these soluble factors, alone or in association, could limit infection of the first placental barrier and/or HIV-1 spread remains to be elucidated. In this study, we asked whether cytokines and chemokines secreted by placental tissue and supernatants of placental explants containing the same cytokines and chemokines could control infection of trophoblastic barriers inoculated with HIV-1+ PBMCs.