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 6

HTLV-1–infected trophoblasts induce de novo infection in humanized mice.

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HTLV-1–infected trophoblasts induce de novo infection in humanized mice....
(A) Schematic of the experimental schedule. After humanization, 9 mice were inoculated i.p. with HTLV-1–harboring placental cells at 0 dpi (VT, n = 3; VMF, n = 3; PVEC, n = 3). Arrowheads indicate the time points of blood collection. All mice were observed carefully during the experimental period at 42 dpi. (B) Cell surface expression level of HTLV-1 envelope glycoprotein was analyzed in primary placental cells cocultured with MT-2 cells. The cells were stained with anti–HTLV-1 gp46 mAb or mouse IgG1 mAb as an isotype control. Representative cells (left) and the percentages of HTLV-1 gp46–positive cells (right) are shown. Data are means ± SD of 3 independent experiments. (C) Quantification of HTLV-1 PVL in the peripheral blood of inoculated mice. HTLV-1 PVL was determined by real-time PCR at 14, 28, and 42 dpi. One dot represents the result of an individual mouse. Undetected samples were given an arbitrary value of 100. (D and E) Human CD45+ leucocytes, CD3+ lymphocytes, total CD4+ T cells, and CD25+ T cells were routinely analyzed by flow cytometry. One dot represents the result of an individual mouse. The absolute numbers of human CD45+ leucocytes are shown in D. Frequencies of lymphocytes positive for the indicated marker are shown in E. CD3+ lymphocytes were gated to analyze the populations of CD4+ and CD25+ T cells. Asterisks represent significant differences versus the data for VTs in B, or PVEC-inoculated mice in C–E. *P < 0.05, **P < 0.01 by 1-way ANOVA followed by Dunnett’s multiple-comparisons test. ND, not detected.