Role of Placental Cytokines in Transcriptional Modulation of HIV Type 1 in the Isolated Villous Trophoblast

Abstract

During pregnancy, a complex cytokine network is present at the maternal-fetal interface in order to support normal growth and development of the placenta and fetus. HIV can frequently infect placental trophoblast but the impact of cytokines produced locally by the placenta and decidua on virus expression and replication is unknown. We comprehensively assayed the cytokines typically present in the placental microenvironment for their potential to modulate HIV transcriptional activation in the isolated trophoblast cells employing a transient transfection assay with luciferase as a reporter gene. Long terminal repeats (LTRs) of two divergent virus strains, HIV-1 LAI and HIV-1 NDK, were used to analyze virus-specific features. Four cytokines, epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF-alpha), were found to stimulate promoters of both viruses, whereas interferon alpha (IFN-alpha) and IFN-beta were found to suppress the transcription driven from both promoters. The differences observed between the two viruses did not reach a statistically significant level. None of the remaining cytokines, including EGF; GM-CSF; insulin-like growth factor I (IGF-I); IFN-alpha, IFN-beta, and IFN-gamma; IL-1 alpha, IL-1 beta, IL-2, IL-6, and IL-10; leukemia inhibitory factor (LIF); macrophage colony-stimulating factor (M-CSF); platelet-derived growth factor BB (PDGF-BB); transforming growth factor beta (TGF-beta); and TNF-alpha, affected transcriptional expression of the promoter constructs. Our results demonstrate that the local balance of cytokines may be critical for activation of HIV in the syncytiotrophoblast-cytotrophoblast layer and thus play an important role in the transmission of virus across the placental barrier.

The Low Viral Production in Trophoblastic Cells Is Due to a High Endocytic Internalization of the Human Immunodeficiency Virus Type 1 and Can Be Overcome by the Pro-inflammatory Cytokines Tumor Necrosis Factor-α and Interleukin-1

“…Interestingly, the same cytokines also induced viral transcription in trophoblastic cells exposed to replication-defective reporter viruses bearing HIV-1 Ada-M or HXB2 envelope glycoproteins. These findings are supported by a recent study (44) showing that HIV-1 LTR activity is increased by TNF-␣ and IL-1␤ in primary isolated human trophoblast cells that were transiently transfected with an HIV-1-based reporter vector. Data from this study were entirely based on transient transfection of HIV-1 LTR-based reporter constructs in trophoblast cells.…”

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

“…Furthermore, the present data showing that PBMCs incubated overnight with PSF and then inoculated with HIV-1 produced 100 to 1,000 times less virus than untreated PBMCs further support a role of PSF in con- trolling spreading of HIV-1 through the placenta, after passage across the trophoblastic barrier. We addressed the question of whether this anti-HIV-1 activity was related to IFN-like activity in PSF since previous studies demonstrated that placental cells secreted this antiviral cytokine (19,33). Thus, the level of secretion and the mRNA content of several forms of IFN in both placental tissue and PSF were evaluated.…”

“…In contrast, expression of inflammatory cytokines is elevated in trophoblasts with a high level of HIV transcripts (18). Along with these findings, interleukin-1␤ (IL-1␤) and tumor necrosis factor alpha (TNF-␣) 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-␣) and IFN-␤ 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).…”

Role of placenta in the vertical transmission of human immunodeficiency virus

“…55 Interferon-a (IFN-a) and IFN-b inhibit the HIV transcription. 56 A connection between in utero vertical transmission of HIV-1 and expression of Th2 cytokines (IL-4 and IL-10) and LIF has been described. 25,52 Whether these factors may possibly limit HIV-1 infection of the trophoblasts remains to be clarified.…”