HTLV-1 targets human placental trophoblasts in seropositive pregnant women
Kenta Tezuka, … , Kiyonori Miura, Isao Hamaguchi
Kenta Tezuka, … , Kiyonori Miura, Isao Hamaguchi
Published October 19, 2020
Citation Information: J Clin Invest. 2020;130(11):6171-6186. https://doi.org/10.1172/JCI135525.
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Research Article Infectious disease Virology

HTLV-1 targets human placental trophoblasts in seropositive pregnant women

Abstract

Human T cell leukemia virus type 1 (HTLV-1) is mainly transmitted vertically through breast milk. The rate of mother-to-child transmission (MTCT) through formula feeding, although significantly lower than through breastfeeding, is approximately 2.4%–3.6%, suggesting the possibility of alternative transmission routes. MTCT of HTLV-1 might occur through the uterus, birth canal, or placental tissues; the latter is known as transplacental transmission. Here, we found that HTLV-1 proviral DNA was present in the placental villous tissues of the fetuses of nearly half of pregnant carriers and in a small number of cord blood samples. An RNA ISH assay showed that HTLV-1–expressing cells were present in nearly all subjects with HTLV-1–positive placental villous tissues, and their frequency was significantly higher in subjects with HTLV-1–positive cord blood samples. Furthermore, placental villous trophoblasts expressed HTLV-1 receptors and showed increased susceptibility to HTLV-1 infection. In addition, HTLV-1–infected trophoblasts expressed high levels of viral antigens and promoted the de novo infection of target T cells in a humanized mouse model. In summary, during pregnancy of HTLV-1 carriers, HTLV-1 was highly expressed in placental villous tissues, and villous trophoblasts showed high HTLV-1 sensitivity, suggesting that MTCT of HTLV-1 occurs through the placenta.

Authors

Kenta Tezuka, Naoki Fuchi, Kazu Okuma, Takashi Tsukiyama, Shoko Miura, Yuri Hasegawa, Ai Nagata, Nahoko Komatsu, Hiroo Hasegawa, Daisuke Sasaki, Eita Sasaki, Takuo Mizukami, Madoka Kuramitsu, Sahoko Matsuoka, Katsunori Yanagihara, Kiyonori Miura, Isao Hamaguchi

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Figure 7

Detection of HTLV-1–infected placental trophoblasts in vivo.

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Detection of HTLV-1–infected placental trophoblasts in vivo. (A) Simulta...
(A) Simultaneous detection of 2 target genes within the same placental villous sections using RNA ISH duplex assay. Probes targeting HTLV-1 minus-strand mRNAs (HBZ) and KRT7, a trophoblast marker, were used to stain the tissue sections of pregnant carriers. The carriers with placental villous PVL (placental villous PVL–positive, and cord blood PVL–negative or –positive) were identical to those in Figure 4 and listed in Table 2. KRT7 was detected using DAB chromogen (brown), and HBZ was detected using fast red chromogen (red). ISH results are shown in the groups of subjects with HTLV-1–negative and –positive cord blood samples (nos. 8 and 10 vs. nos. 13 and 16). (B) RNA ISH combined with immunofluorescence (IF) assay was performed as a confirmatory test. KRT7 protein was detected using FITC (green), HBZ was detected using fast red as a fluorochrome (red), and cell nuclei were stained with NucBlue (blue). Black boxes in A and white boxes in B represent 25 μm squares and 50 μm squares, respectively, and indicate the regions shown at a higher magnification in the same panels. In A and B, data are representative of at least 2 nonserial tissue sections. (C) Quantitative evaluation of RNA ISH combined with IF results. The total number of HBZ probe–positive foci in KRT7-positive or -negative cells of each section was counted by fluorescence microscopy. Data are mean ± SD values from 6 tissue sections of each group. The multiple t test was performed to compare statistical differences between groups in subjects with HTLV-1–negative and –positive cord blood samples (nos. 7–12 vs. nos. 13–18). Asterisks in C represent significant differences between KRT7-negative and KRT7-positive cells; **P < 0.01 by Mann-Whitney U-test.