Molecular epidemiology of endemic Human T-Lymphotropic virus 1 (HTLV-1) in a community in rural Guinea-Bissau

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Maternal proviral load and vertical transmission of Human T cell Lymphotropic Virus type 1 in Guinea-Bissau

The relative importance of routes of transmission of human T cell lymphotropic virus type 1 (HTLV-1) in Guinea-Bissau is largely unknown; vertical transmission is thought to be important, but there are very few existing data. We aimed to examine factors associated with transmission in mothers and children in Guinea-Bissau, where HTLV-1 is endemic (prevalence of 5% in the adult population). A cross-sectional survey was performed among mothers and their children (aged <15 years) in a rural community in Guinea-Bissau. A questionnaire to identify risk factors for infection and a blood sample were obtained. HTLV-1 proviral load in peripheral blood was determined and PCR was performed to compare long terminal repeat (LTR) sequences in mother-child pairs. Fourteen out of 55 children (25%) of 31 HTLV-1-infected mothers were infected versus none of 70 children of 30 uninfected mothers. The only factor significantly associated with HTLV-1 infection in the child was the proviral load of the mother; the risk of infection increased significantly with the log(10) proviral load in the mother's peripheral blood (OR 5.5, 95% CI 2.1-14.6, per quartile), adjusted for weaning age and maternal income. HTLV-1 sequences of the LTR region obtained from mother-child pairs were identical within pairs but differed between the pairs. Vertical transmission plays an important role in HTLV-1 transmission in this community in Guinea-Bissau. The risk of transmission increases with the mother's proviral load in the peripheral blood. Identical sequences in mother-child pairs give additional support to the maternal source of the children's infectio

Molecular Epidemiology of Endemic Human T-Lymphotropic Virus Type 1 in a Rural Community in Guinea-Bissau

Human T-Lymphotropic Virus type 1 (HTLV-1) affects millions of people worldwide. It is very similar to Simian T-Lymphotropic Virus, a virus that circulates in monkeys. HTLV-1 causes a lethal form of leukemia (Adult T-cell Leukemia) and a debilitating neurological syndrome (HTLV-associated myelopathy/tropical spastic paraparesis) in approximately 5% of infected people. Based on sequence variation, HTLV-1 can be divided into 7 subtypes (1a–1g) with the Cosmopolitan subtype 1a further subdivided into subgroups (A–E). We examined HTLV-1 diversity in a rural area in Guinea-Bissau, a country in West Africa with a high HTLV-1 prevalence (5%). We found that most viruses belong to the Cosmopolitan subtype 1a, subgroup D, but 2 viruses belonged to subtype 1g. This subtype had thus far only been found in monkey hunters in Cameroon, who were probably recently infected by monkeys. Our findings indicate that this subtype has spread beyond Central Africa. An important, unresolved question is whether persons with this subtype were infected by monkeys or through human-to-human transmission

ML tree of 630-bp LTR sequences from 48 Caio infected subjects (Caio sequences in red).

<p>Also included are 66 STLV/HTLV-1 reference sequences (in black); Mel5 was used as an outgroup. The names of the countries of origin are denoted in brackets (CAR, Central African Republic). The phylogenetic tree was inferred under a Tamura-Nei evolutionary model with a gamma model of among-site substitution rate heterogeneity. Bootstrap values using 1000 replicates of ≥60 are indicated on the branches. The asterisks indicate significant branch length on ML testing (* p-value≤0.001; ** p-value≤0.05). The scale bar represents the number of nucleotide substitutions per site. The scale of the MarB43 is not on scale because it did not fit in the figure. Sequences identical to Caio4676 are Caio4126, Caio4142, Caio4315, Caio4768, Caio5324, Caio5801, Caio6460, Caio6936 and Caio7120. Sequence identical to Caio4647 is Caio4650. Sequence identical to Caio4799 is Caio4801. Sequences identical to Caio5620 are Caio4743, Caio4745 and Caio5883. Sequences identical to Caio5187 are Caio5846, Caio5884 and Caio5931. Sequences identical to Caio4634 are Caio4635 and Caio5448. Sequences identical to Caio4758 are: Caio4658, Caio4659 and Caio4757. Sequence identical to Caio4671 is Caio4702. Sequences identical to 7580 are 7421 and 7661. Only one example of each set of identical sequences was included in the analysis.</p

ML tree of 647-bp p24 sequences from 36 Caio infected subjects (Caio sequences in red).

<p>Also included are 15 STLV/HTLV-1 reference sequences (in black); Mel5 was used as an outgroup. The countries of origin are denoted in brackets (CAR, Central African Republic; NA, not available). The phylogenetic tree was inferred under a Tamura-Nei evolutionary model with a gamma model of among-site substitution rate heterogeneity. Bootstrap values using 1000 replicates of ≥60 are indicated on the branches. The asterisks indicate significant branch length on ML testing (* p-value≤0.001; ** p-value≤0.05). The scale bar represents the number of nucleotide substitutions per site. Sequences identical to Caio4009 are Caio4072, Caio4106, Caio4112, Caio4211, Caio4315, Caio4328, Caio4358, Caio4383, Caio4417, Caio4418, Caio5801, Caio6473, Caio6590, Caio65396 and Caio65407. Sequence identical to Caio65363 is Caio65571. Sequence identical to Caio4258 is Caio65325. Only one example of each set of identical sequences was included in the analysis.</p

Primers used for HTLV-1 LTR and p24 PCR and sequencing.

<p>OF, outer forward; OR, outer reverse; IF, inner forward; IR, inner reverse.</p><p>Primers MO195-MO202 based on, but not identical to primers described in Salemi et al. <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001690#pntd.0001690-Salemi1" target="_blank">[21]</a>.</p

Characteristics of subjects of whom HTLV-1 LTR and/or p24 sequences were obtained from Caió, Guinea-Bissau, 2003–2007.

<p>IQR, interquartile range.</p

Neurogenic differentiation by hippocampal neural stem and progenitor cells is biased by NFIX expression

© 2018. Published by The Company of Biologists Ltd. Our understanding of the transcriptional programme underpinning adult hippocampal neurogenesis is incomplete. In mice, under basal conditions, adult hippocampal neural stem cells (AH-NSCs) generate neurons and astrocytes, but not oligodendrocytes. The factors limiting oligodendrocyte production, however, remain unclear. Here, we reveal that the transcription factor NFIX plays a key role in this process. NFIX is expressed by AH-NSCs, and its expression is sharply upregulated in adult hippocampal neuroblasts. Conditional ablation of Nfix from AH-NSCs, coupled with lineage tracing, transcriptomic sequencing and behavioural studies collectively reveal that NFIX is cell-autonomously required for neuroblast maturation and survival. Moreover, a small number of AH-NSCs also develop into oligodendrocytes following Nfix deletion. Remarkably, when Nfix is deleted specifically from intermediate progenitor cells and neuroblasts using a Dcx-creERT2driver, these cells also display elevated signatures of oligodendrocyte gene expression. Together, these results demonstrate the central role played by NFIX in neuroblasts within the adult hippocampal stem cell neurogenic niche in promoting the maturation and survival of these cells, while concomitantly repressing oligodendrocyte gene expression signatures