It is thought that human T-cell lymphotropic virus type I (HTLV-I IntroductionHuman T-cell lymphotropic virus type I (HTLV-I), the first human retrovirus to be discovered, was isolated originally from the cultured CD4 ϩ T lymphocytes of a patient with cutaneous T-cell lymphoma. 1 Soon after, HTLV-III/lymphadenopathy-associated virus was identified 2,3 and subsequently renamed human immunodeficiency virus type 1 (HIV-1). These retroviruses predominantly infect CD4 ϩ cells, 4,5 an observation that directly led to defining CD4 as a receptor for HIV-1. 6,7 HTLV-I can cause a CD4 ϩ T-cell malignancy termed adult T-cell leukemia/lymphoma (ATL) 8 and an inflammatory neurologic disease called HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). 9,10 More recently, other disorders have been associated with HTLV-I infection, including arthropathy, 11 alveolitis, 12 myositis, 13 and uveitis. 14 Although the receptor for HTLV-I has not been identified, it is believed to be expressed on many cell types 15 because HTLV-I infects a wide range of cells in vitro, including endothelial cells and fibroblasts. 16,17 HTLV-I has been thought to preferentially infect CD4 ϩ T cells in vivo. 18 Studies demonstrating that the surface phenotype of typical ATL cells is CD4 ϩ19 supported the finding that CD4 ϩ T cells were highly susceptible to HTLV-I. Mechanistically, HTLV-I is thought to transform infected CD4 ϩ T cells through transactivation of host cellular genes by the HTLV-I Tax protein. 20 Peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients are known to proliferate spontaneously in vitro, 21 and it has been suggested that the HTLV-I Tax protein in HTLV-I-infected CD4 ϩ T cells transactivates interleukin (IL)-2 and its receptor, which is associated with this spontaneous lymphoproliferation. 22 A few studies using polymerase chain reaction (PCR) suggested that non-CD4 ϩ T cells were also infected with HTLV-I in vivo. 23,24 However, the studies remain controversial because of the difficulty of excluding contamination with HTLV-I-infected CD4 ϩ cells. In addition, the accuracy of quantitative PCR was not sufficient to allow firm conclusions.Recently, a reliable and accurate real-time quantitative PCR technique (Taqman, Applied Biosystems, Foster City, CA) was developed. 25 HTLV-I (pX) proviral load in HAM/TSP patients was assessed using this technology, and an extraordinarily high proviral load was demonstrated in these patients, ranging from 1.72 to 70.86 copies per 100 PBMCs. Two possibilities were considered to account for such a high proviral burden. First, HTLV-I may have infected other cell types in addition to CD4 ϩ T cells. Second, multiple HTLV-I copies may infect a single cell. In support of the former hypothesis, we have shown that in PBMCs from HAM/TSP patients, both CD4 ϩ and CD8 ϩ T cells spontaneously proliferated. Moreover, the percentage of proliferating CD8 ϩ T cells was 2 to 5 times higher than that of CD4 ϩ T cells. 26 Given this observation of the high HTLV-I proviral load in PBMCs from ...

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The optic chiasm is an important choice point at which retinal ganglion cell (RGC) axons either cross the midline to innervate the contralateral brain or turn back to innervate the ipsilateral brain. Guidance cues that regulate this decision, particularly those directing the midline crossing of contralateral axons, are still not well understood. Here we show that Sema3d, a secreted semaphorin expressed at the midline, guides the crossing of RGC axons in zebrafish. Both Sema3d knockdown and ubiquitous overexpression induced aberrant ipsilateral projections, suggesting that Sema3d normally guides axons into the contralateral optic tract. Live imaging in vivo showed that RGC growth cones responded to ubiquitous Sema3d overexpression by pausing for extended periods and increasing their exploratory behavior at the midline, suggesting that Sema3d overexpression causes the midline environment to become less favorable for RGC axon extension. Interestingly, Sema3d overexpression did not affect growth cone behaviors before the midline, suggesting that RGC axons normally respond to Sema3d only upon reaching the midline. After Sema3d knockdown, growth cones grew across the midline but then paused or repeatedly retracted, impairing their ability to leave the midline region. Our results indicate that a proper balance of Sema3d is needed at the midline for the progression of RGC axons from the chiasm midline into the contralateral optic tract.