Persistent Human T-Lymphotropic Virus Type 1 (HTLV-1) Infection in the Placenta of Pregnant Women

Abstract

Mother-to-child transmission (MTCT) is the primary route of human T-lymphotropic virus type 1 (HTLV-1) infection. Although formula feeding reduces breastfeeding-associated transmission, MTCT still occurs, implicating pregnancy or delivery as key transmission windows. In this study, placental tissues from nine HTLV-1-positive mothers were analyzed using DNA/RNAscope, revealing low HTLV-1 DNA and RNA levels and a low RNA/DNA ratio, consistent with latent infection in the placenta and potentially explaining the low MTCT rate. Elevated interferon (IFN)-β levels were observed in infected placentas compared to seronegative controls, while IFNα, IFNγ, and IFITM expression remained unchanged. Concurrently, sustained IFNβ expression in infected placentas suggests its dual roles in HTLV-1 pathogenesis: suppressing viral replication while potentially disrupting placental homeostasis through chronic inflammation. In vitro modeling using BeWo cells or primary trophoblasts cocultured with HTLV-1-infected MT-2 cells demonstrated syncytin-1-mediated viral entry, confirmed by HTLV-1 p19 detection in both trophoblasts. Of note, HTLV-1 transmission was abolished by a syncytin-1-specific fusion inhibitor HRB1, underscoring syncytin-1's essential role in cell-to-cell transmission of HTLV-1. Thus, this study identifies syncytin-1 as a therapeutic target to block vertical transmission and highlights the need to balance antiviral responses with placental integrity in HTLV-1 management.

Keywords: HERV‐W1 Env; HTLV‐1; IFNβ; placenta; spontaneous abortions; syncytin‐1.

Figure 1

The detection of HTLV‐1 gag DNA in the placenta. (A) HTLV‐1 gag DNA in different placental regions was visualized using in situ RNAscope hybridization in combination with immunofluorescence assay of trophoblast marker protein CK7 (Scale bar, 250 μm). Red, HTLV‐1 RNA; Green, trophoblast marker CK7. (B) HTLV‐1 gag DNA was quantitated in the decidua, intervillar space, villi, and trophoblasts (n = 7).

Figure 2

The detection of HTLV‐1 HBZ RNA in the placenta. (A) HTLV‐1 HBZ RNA in different placental regions was visualized using in situ DNAscope hybridization in combination with immunofluorescence assay of trophoblast marker protein CK7 (Scale bar, 250 μm). Red, HTLV‐1 RNA; Green, trophoblast marker CK7. (B) HTLV‐1 HBZ RNA was quantitated in the decidua, intervillar space, villi, and trophoblasts (n = 7).

Figure 3

The detection of HTLV‐1 Tax RNA in the placenta. (A) HTLV‐1 Tax RNA in different placental regions was visualized using in situ DNAscope hybridization in combination with immunofluorescence assay of trophoblast marker protein CK7 (Scale bar, 250 μm). Red, HTLV‐1 RNA; Green, trophoblast marker CK7. (B) HTLV‐1 HBZ RNA was quantified in the decidua, intervillar space, villi, and trophoblasts (n = 7). (C) The ratio of HTLV‐1 RNA/DNA in the placenta.

Figure 4

IFNβ enrichment in the placenta from HTLV‐1‐infected mothers. The expression of (A) syncytin‐1, (B) IFNα, (C) IFNβ, (D) IFNγ, and (E) IFITM in placental tissues from HTLV‐1‐seropositive and HTLV‐1‐seronegative mothers was analyzed by ddPCR (n = 9).

Figure 5

Previous spontaneous abortion (SAB) in HTLV‐1–infected mothers was not associated with placental expression of syncytin‐1, IFN‐β, IFN‐γ, or IFITM. (A) Syncytin‐1 in the human placenta was visualized by immunohistochemistry in the trophoblast border (Term placenta villi at 36–41 weeks of pregnancy) in the dark brown. Scale bar, 200 μm. (B) The expression of syncytin‐1, IFNα, IFNβ, IFNγ, or IFITM in the placenta from HTLV‐1‐infected women with or without previous SAB was measured by ddPCR.

Figure 6

Syncytin‐1 may mediate HTLV‐1 infection of placental trophoblasts. (A) Expression of syncytin‐1 receptors ASCT1 and ASCT2 on MT‐2 cells was measured by flow cytometry. (B) A schematic diagram of the coculture protocol for HTLV‐1 transfer to trophoblasts. BeWo cells or PCTs were cocultured with MT‐2 cells (10:1 ratio of MT‐2 and target cells) for 48 h, followed by washing and further incubation. (C) Representative phase‐contrast images (scale bar = 200 μm) show reduced confluency in BeWo cells cocultured with MT‐2 cells. (D) Protein levels of HTLV‐1 p19, syncytin‐1, and β‐actin in BeWo cells and PCTs under basal conditions or after forskolin induction (20–50 μM for BeWo; 50–100 μM for PCTs), with or without HRB1‐mediated syncytin‐1 cell fusion blockade. The relative intensity of p19 expression is shown below with data normalized to the BeWo or PCT cocultured with MT‐2 cells without forskolin treatment. Syncytin‐1 expression was normalized to the corresponding group without forskolin treatment.