S907 DEVELOPMENT OF HUMANIZED MOUSE MODEL FOR STUDYING MOTHER TO CHILD HTLV‐1 TRANSMISSION AND PREVENTION WITH HTLV‐1 ANTIBODY TREATMENT
Authors: Mizukami T. , Nojima K. , Sato Y. , Furuhata K. , Sasaki E. , Matsuoka S. , Okuma K. , Moriuchi H. , Uchimaru K. , Akari H. , Satake M. , Hamaguchi I. 
Published: June 2019

Background:

Human T‐cell leukemia virus type 1 (HTLV‐1) infects mature T cells and causes adult T‐cell leukemia (ATL) and a chronic inflammatory central nervous system disease called HAM/TSP. HTLV‐1 transmissions mainly occurred in children via the breast milk of HTLV‐1+ carrier mothers. Thus, bottle‐feeding or avoiding long term breastfeeding are recommended in the endemic areas of Japan and this resulted in a drastic decrease in new HTLV‐1 infections. Previous studies have shown that approximately 3% of children born from HTLV‐1+ carrier mothers were still infected even when they were exclusively bottle‐fed. This suggested the possible involvement of alternative HTLV‐1 transmission routes, such as placental or birth canal transmission.

Aims:

Here, we attempted to develop new humanized mouse model of HTLV‐1 mother to child (MTC) transmission for evaluating HTLV‐1 antibody to prevent HTLV‐1 MTC infection.

Methods:

NOD/SCID/gammac (null) (NOG) pregnant mice were intraperitoneally injected with human PBMCs before being transplanted with a mitomycin C‐treated HTLV‐1‐infected cell line (MT‐2). To evaluate the importance of HTLV‐1 infections via breastfeeding or before birth, we designed a study that switched HTLV‐1‐infected carrier mother (CM) mice with non‐infected healthy mother (HM) mice. HTLV‐1 infection was determined by the real‐time PCR quantification of HTLV‐1 DNA isolated from mouse liver, peripheral blood and breastmilk.

Results:

Although no HTLV‐1‐infected T cells were detected in the peripheral blood of newborn mice at day 14, HTLV‐1‐infected cells were exclusively observed in the liver tissues via FACS and PCR. Furthermore, highly enriched HTLV‐1+ cells were still detected in mouse breast milk 26 days after birth by PCR. These data suggest that there might be an enrichment system of HTLV‐1 infectious cells in mouse breast tissue. We next performed the mother‐pup pair switching study. After switching, CM mice were maintained with HM mice pups (potentially HTLV‐1−), and HM mice were maintained with CM mice pups (potentially HTLV‐1+). This switching at birth resulted in 28% of the potentially HTLV‐1− pups to become HTLV‐1+, since they were breastfed by an HTLV‐1+ mother. Similarly, 42% of the potentially HTLV‐1+ pups were HTLV‐1+ at 40 days after switching, as they were breastfed by an HTLV‐1− mother. These results suggested that both breastfeeding and canal or placental transmissions presented equal risks with respect to HTLV‐1 infections. We finally analyzed the HTLV‐1 infectious status both in mouse embryo and placenta at E17.5 and found HTLV‐1+ cells both in fetal liver (25%) and placenta (37%).

Summary/Conclusion:

Together, these data suggest that during pregnancy, HTLV‐1 cells invade the fetal tissues and might be a potential resource of HTLV‐1 infection. We are now trying to assess the effect of HTLV‐1 antibody for preventing MTC HTLV‐1 infection.