Human T-cell Leukemia Virus Type I Carriers Research Articles

Evaluating mRNA expression of tax, B chain of PDGFand PDGF-β receptorsas well as HTLV-I proviral load in ATL patients and healthy carriers.

Adult T-cell leukemia (ATL) is a life-threatening malignant neoplasm of CD4+ T cells resulted from human T-cell leukemia virus type I (HTLV-I). Tax1 protein of HTLV-I can induce malignant proliferation of T-cells bymodulating the expression of growth factors such as platelet-derived growth factor (PDGF). Here, we aimed to investigate the proviral load (PVL) of HTLV-I in ATLand also to evaluate the mRNA expression of B chain of PDGF and PDGF-β receptors in ATL patients and HTLV-I-infected healthy carriers. To this end, peripheral blood mononuclear cells (PBMCs) were isolated by using Ficoll-Histophaque density centrifugation. The mean of HTLV-I PVL in ATL patients (42,759 ± 15,737 copies/104 cells [95% CI, 9557-75962]) was significantly (p = .01) higher than that in healthy carriers (650 ± 107 copies/104 cells [95% CI, 422-879], respectively. The HTLV-I PVL in ATL patients exhibited a significant correlation with PBMC count (R = .495, p = .001). The mRNA expression of Tax, B chain of PDGF, and PDGF-β receptor genes was significantly higher in healthy carriers than in patients with ATL. In conclusion, the expression of the canonical PDGFβ and its receptor, and their correlation with Tax expression cannot be a suitable indicator and/or prognostic factor for progression of ATL in HTLV-I carriers.

Metabolic abnormalities in adult T-cell leukemia/lymphoma and induction of specific leukemic cell death using photodynamic therapy

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Therapeutic interventions have not been associated with satisfactory outcomes. We showed that the porphyrin metabolic pathway preferentially accumulates the endogenous photosensitive metabolite, protoporphyrin IX (PpIX) in ATL, after a short-term culture with 5-aminolevulinic acid (ALA). PpIX accumulated 10–100-fold more in ATL leukemic cells when compared to healthy peripheral blood mononuclear cells (PBMCs). Patient specimens showed dynamic changes in flow cytometry profiles during the onset and progression of ATL. Furthermore, 98.7% of ATL leukemic cell death in the ATL patient specimens could be induced with 10 min of visible light exposure, while 77.5% of normal PBMCs survived. Metabolomics analyses revealed that a specific stage of the metabolic pathway progressively deteriorated with HTLV-I infection and at the onset of ATL. Therefore, this method will be useful in diagnosing and identifying high-risk HTLV-I carriers with single cell resolutions. Photodynamic therapy in the circulatory system may be a potential treatment due to its highly-specific, non-invasive, safe, simultaneous, and repeatedly-treatable modalities.

Heat Shock Enhances the Expression of the Human T Cell Leukemia Virus Type-I (HTLV-I) Trans-Activator (Tax) Antigen in Human HTLV-I Infected Primary and Cultured T Cells

The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS. HS treatment at 43 °C for 30 min for 24 h led to marked increases in the level of Tax antigen expression in all HTLV-I-infected T cell lines tested including a number of HTLV-I-naturally infected T cell lines. HS also increased the expression of functional HTLV-I envelope gp46 antigen, as shown by increased syncytium formation activity. Interestingly, the enhancing effect of HS was partially inhibited by the addition of the heat shock protein 70 (HSP70)-inhibitor pifithlin-μ (PFT). In contrast, the HSP 70-inducer zerumbone (ZER) enhanced Tax expression in the absence of HS. These data suggest that HSP 70 is at least partially involved in HS-mediated stimulation of Tax expression. As expected, HS resulted in enhanced expression of the Tax-inducible host antigens, such as CD83 and OX40. Finally, we confirmed that HS enhanced the levels of Tax and gp46 antigen expression in primary human CD4+ T cells isolated from HTLV-I-infected humanized NOD/SCID/γc null (NOG) mice and HTLV-I carriers. In summary, the data presented herein indicate that HS is one of the environmental factors involved in the reactivation of HTLV-I in vivo via enhanced Tax expression, which may favor HTLV-I expansion in vivo.

Human T-cell leukemia virus type-I Tax induces the expression of CD83 on T cells.

BackgroundCD83, a cell surface glycoprotein that is stably expressed on mature dendritic cells, can be transiently induced on other hematopoietic cell lineages upon cell activation. In contrast to the membrane form of CD83, soluble CD83 appears to be immunosuppressive. In an analysis of the phenotype of leukemic CD4+ T cells from patients with adult T-cell leukemia (ATL), we found that a number of primary CD4+ T cells became positive for cell surface CD83 after short-term culture, and that most of these CD83+ CD4+ T cells were positive for human T-cell leukemia virus type-I (HTLV-I) Tax (Tax1). We hypothesized that Tax1 is involved in the induction of CD83.ResultWe found that CD83 was expressed selectively on Tax1-expressing human CD4+ T cells in short-term cultured peripheral blood mononuclear cells (PBMCs) isolated from HTLV-I+ donors, including ATL patients and HTLV-I carriers. HTLV-I-infected T cell lines expressing Tax1 also expressed cell surface CD83 and released soluble CD83. CD83 can be expressed in the JPX-9 cell line by cadmium-mediated Tax1 induction and in Jurkat cells or PBMCs by Tax1 introduction via infection with a recombinant adenovirus carrying the Tax1 gene. The CD83 promoter was activated by Tax1 in an NF-κB-dependent manner. Based on a previous report showing soluble CD83-mediated prostaglandin E2 (PGE2) production from human monocytes in vitro, we tested if PGE2 affected HTLV-I propagation, and found that PGE2 strongly stimulated expression of Tax1 and viral structural molecules.ConclusionsOur results suggest that HTLV-I induces CD83 expression on T cells via Tax1 -mediated NF-κB activation, which may promote HTLV-I infection in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0185-1) contains supplementary material, which is available to authorized users.

Mutation Analysis for TP53 in Chronic-Type Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). ATLL is classified into four clinical subtypes based on the clinical manifestation: acute, lymphoma, chronic and smoldering. Approximately half of chronic type ATLL cases progressed to the acute type. We previously demonstrated that genomic alterations related to the cell cycle de-regulation such as CDKN2A and immune escape such as CD58 alteration can serve as predictive biomarkers for acute transformation of the chronic type. Although alteration of TP53, which is known to be a major regulator of cell cycle, has been identified in several types of cancers including acute type ATLL, no copy number alteration of TP53 was found in the chronic type by array comparative genomic hybridization. In the present study, mutation of TP53 was further analyzed by sequencing for these cases as well as HTLV-I carriers with oligo-clonality. However, no TP53 mutation was identified. These results suggested that TP53 mutation plays a role for the later stage of ATLL development.

Epidemiology, clinical features and prevention of HTLV‐I infection

Human T-cell leukemia virus type I (HTLV-I) [1,2] is the main cause of Adult T-cell leukemia ⁄ lymphoma (ATLL) [3] and HTLV-I associated myelopathy ⁄ Tropical spastic paraparesis (HAM ⁄ TSP) [4,5]. From the long-term epidemiological observation, the HTLV-I carriers are clustered in limited groups in the world, i.e., Southwestern Japanese, native Oceanians, Amerindians in Andes and Northeast British Colombia, North Iranians as well as Central Africans and their descendants in the Caribbean basin and South America [6]. According to evidence obtained from a biennial nationwide surveillance of adult T-cell leukemia ⁄ lymphoma (ATLL) carried out in Japan since 1986, the annual incidence is estimated to be 700 within approximately one million HTLV-I carriers in Japan [7]. The affected individuals mainly inhabit the southern and northern ATLL endemic areas. Among 3499 ATLL patients newly diagnosed during the last ten years from 1988 to 1997 [8], approximately 70% were born in the southwestern districts of Kyushu and Shikoku, and 10% in the northern districts of Hokkaido and Tohoku (Fig. 1). This epidemic pattern of ATLL is still continuous up until now. The main reasons of unique geographical clustering of ATLL in Japan might be linked to a history of old Japanese migration with unique geographical clustering of HTLV-I carriers in Japanese archipelago due to the natural transmission routes of mother-to-child through breast milk and man-to-woman through semen [9,10]. In the ATLL endemic areas in Japan a systematic prevention trial against HTLV-I transmission through breast milk from HTLV-I carrying mothers to newborn babies, e.g., strong recommendation to pregnant women with HTLV-I to completely stop breast milk and ⁄ or to raise their babies by short-term breast feeding [11,12]. Clinically contrasting HTLV-I related diseases

Immune responses and serum levels of cytokines in adult T-cell leukemia patients and human T-cell leukemia virus type-I carriers.

To find predictive parameters for development and progression of adult T-cell leukemia (ATL) in human T-cell leukemia virus type-I (HTLV-I) carriers, we investigated cellular immune responses such as mitogenic responses and natural killer activity of the peripheral blood mononuclear cells (PBMC). And serum or plasma levels of cytokines, including tumor-necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and immunosuppressive acidic protein (IAP), were also measured in patients with ATL, healthy HTLV-I carriers and healthy HTLV-I non-carriers as controls. Results are as follows: (1) increased spontaneous proliferation and decreased mitogenic responses of PBMC already existed in HTLV-I carriers; (2) IAP was significantly higher in patients with acute/lymphoma type ATL than in those with chronic/smoldering type, HTLV-I carriers and HTLV-I non-carriers. These results suggest that spontaneous proliferation or mitogenic responses and IAP may be useful parameters for the development and progression of ATL from the carriers. Since HTLV-I carriers already have various grades of immunosuppression, we should seriously try to prevent further HTLV-I transmission.

Immunologic Control of Human T-Cell Leukemia Virus Type I and Adult T-Cell Leukemia

Host T-cell responses to human T-cell leukemia virus type I (HTLV-I) control the expansion of HTLV-I-infected cells and are determinants of the equilibrium proviral load in vivo. Insufficient T-cell responses are regarded as an immunologic risk factor for adult T-cell leukemia (ATL) because they allow increased proviral loads, which represent an epidemiologic risk factor for ATL. ATL cells from approximately half of ATL cases retain the ability to express HTLV-I Tax, a major target antigen of HTLV-I-specific cytotoxic T-lymphocytes (CTL), whereas Tax-specific CTL in ATL patients are inactive. Tax-specific CTL responses are strongly activated after hematopoietic stem cell transplantation in some ATL patients in long-term remission, indicating that HTLV-I Tax is expressed in vivo rather than being silent, and that the donor-derived T-cell system can recognize it. These findings strongly suggest that reactivation of Tax-specific CTL by vaccines may be promising for prophylaxis of ATL in the high-risk group of HTLV-I carriers and for therapy of ATL in patients whose tumor cells are capable of expressing Tax.

Why is the distribution of HTLV-I carriers geographically biased? An answer through a mathematical epidemic model

Human T-cell leukemia virus type I (HTLV-I) is a retrovirus that causes adult T-cell leukemia, and the distribution of HTLV-I carriers is endemically biased, e.g. in Japan the density of carriers is high in Kyushu and Okinawa. In order to consider population dynamics over long times taking account of an increase and a decrease of a population we propose a continuous-time HTLV-I model. The model describes population dynamics of carrier numbers and that of carrier proportions, and theoretical results about an increase and a decrease of carriers are obtained. The present approach derives an explanation of the biased distribution of carriers in Japan.

HTLV-I bZIP Factor Gene, Encoded by the Minus Strand of HTLV-I Provirus, Is Critical for Pathogenesis of HTLV-I Associated Diseases.

Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) in about 5% of carriers after a long latent period. HTLV-I is one of complex retrovirus, which encodes accessory genes to control viral replication and proliferation of infected cells. Previous studies reported the pleiotropic actions of tax gene in proliferation of infected cells and leukemogenesis. However, tax gene expression in ATL cells is disrupted by several mechanisms. Our previous study showed that the 5′-LTR of HTLV-I is frequently hypermethylated or deleted in ATL cells, while the 3′-LTR remains unmethylated and intact. These findings suggest the involvement of the 3′-LTR in leukemogenesis. Transcription from the minus strand of HTLV-I has been reported, and the HTLV-I bZIP factor (HBZ) was subsequently found to inhibit Tax-mediated transactivation of viral gene transcription from the 5′-LTR by heterodimerizing with either CREB2, c-Jun or JunB.Based on these previous studies, we hypothesized that HBZ had an important role in ATL cells. We first identified the transcription start site of HBZ gene in the 3′-LTR and found the novel splicing form. The HBZ gene transcription could be detected in all ATL cases and two of three HTLV-I asymptomatic carriers. Suppression of HBZ gene transcription by short hairpin RNA inhibits proliferation of ATL cells. In addition, HBZ gene expression promotes proliferation of a human T-cell line.Transcriptional profiling showed that BTG2, which is known as an antiproliferative molecule, and MX-1, which has an antiviral function, were down regulated. In addition, HBZ up-regulated the transcription of E2F-1 and its target genes. These results suggest that HBZ is associated with the proliferation and survival of HTLV-I infected cells. Furthermore, HBZ mutant analyses suggested that HBZ promotes T-cell proliferation in its RNA form, while HBZ protein suppresses Tax-mediated viral transcription through the 5′-LTR. The studies of microarrays showed that transcriptional changes by HBZ gene could be categorized into two groups: those caused by HBZ RNA and HBZ protein. HBZ protein enhanced the transcription of cellular genes in transfected cells such as GRAP2, an adaptor molecule in the downstream signaling of T cell receptor, which should be important in pathogenesis by HBZ. To analyze the function of HBZ gene in vivo, we generated transgenic (Tg) mice expressing HBZ under the control of the mouse CD4 promoter/enhancer. The percentage of CD4 T cells increased in splenocytes of the Tg mice. In addition, proliferation induced by cross-linking with an immobilized anti-CD3 antibody was augmented in thymocytes of these Tg mice. These data indicate that the HBZ gene promotes proliferation of CD4 T cells in vivo. Interestingly, one of three strains of HBZ mice spontaneously develops dermatitis at about 3–4 months of age. Histological analyses revealed severe dermatitis with massive dermal and epidermal infiltration of lymphocytes. In other strains of transgenic mice, which did not present dermatitis, infiltration of lymphocytes was also observed. In HTLV-I carriers with high provirus loads, infiltration of CD4 T-lymphocytes into the skin has been reported. The spontaneous dermatitis in the HBZ mice resembles to that observed in HTLV-I infected individuals. Taken together, these data suggest that HBZ gene is implicated not only in oncogenesis by HTLV-I, but also in HTLV-I associated diseases.

Adult T-cell Leukemia Development From a Human T-cell Leukemia Virus Type I Carrier After a Living-Donor Liver Transplantation

Adult T-cell leukemia (ATL) develops in a human T-cell leukemia virus type I (HTLV-I) carrier. The development of malignancy during immunosuppressive treatment following organ transplantation is one of the late fatal complications. We describe the development of three cases of ATL in eight HTLV-I carriers within 164 living-donor liver transplant recipients undergoing immunosuppressive treatment. All three cases were immunosuppressed with tacrolimus. Acute-type ATL was diagnosed at 6, 9, and 25 months after living-donor liver transplantation, based on increased numbers of CD4+25+ lymphocytes exhibiting "flower-like" nuclei, and the elevation of lactate dehydrogenase. Southern blot analysis demonstrated the clonal proliferation of ATL cells in peripheral blood. The ATL cells originated from the recipient, as demonstrated by fluorescence in situ hybridization analysis using sex chromosomal markers. Our observations suggest that immunosuppressive treatment for the prevention of graft rejection after living-donor liver transplantation may induce the development of ATL in an HTLV-I carrier.

Human T Cell Leukemia Virus Type I-Infected Patients with Hashimoto’s Thyroiditis and Graves’ Disease

Autoimmune thyroid diseases have been reported to be associated with human T cell leukemia virus type I (HTLV-I) infection. HTLV-I proviral load is related to the development of HTLV-I-associated myelopathy/tropical spastic paraparesis and has also been shown to be elevated in the peripheral blood of HTLV-I-infected patients with uveitis, arthritis, and connective tissue disease. The objective of the study was to evaluate the proviral load in HTLV-I-infected patients with Hashimoto's thyroiditis (HT) or Graves' disease (GD) and ascertain the ability of HTLV-I to infect thyroid cells. A quantitative real-time PCR assay was developed to measure the proviral load of HTLV-I in peripheral blood mononuclear cells from 26 HTLV-I-infected patients with HT, eight HTLV-I-infected patients with GD, or 38 asymptomatic HTLV-I carriers. Rat FRTL-5 thyroid cells were cocultured with HTLV-I-infected T cell line MT-2 or uninfected T cell line CCRF-CEM. After coculture with T cell lines, changes in Tax and cytokine mRNA expression were studied by RT-PCR. HTLV-I proviral load was significantly higher in the peripheral blood of patients with HT and GD than asymptomatic HTLV-I carriers. In the peripheral blood from HTLV-I-infected patients with HT, HTLV-I proviral load did not correlate with the thyroid peroxidase antibody or thyroglobulin antibody titer. After coculture with MT-2 cells, FRTL-5 cells expressed HTLV-I-specific Tax mRNA. These cocultured FRTL-5 cells with MT-2 cells expressed IL-6 mRNA and proliferated more actively than those cocultured with CCRF-CEM cells. Our findings suggest the role of the retrovirus in the development of autoimmune thyroid diseases in HTLV-I-infected patients.

CHANGES IN HTLV-I POSITIVE RATES AMONG PREGNANT WOMEN IN OKINAWA PRIOR TO THE EFFECTS OF MEASURES INTRODUCED TO PREVENT VERTICAL TRANSMISSION THROUGH BREAST MILK FEEDING

Objectives: Human T cell leukemia virus type-I (HTLV-I) is a causative agent of human T-cell leukemia and HTLV-I associated myelopathy (HAM/TSP). HTLV-I carriers are often infected vertically, especially via mother's milk. Since 1985, clinical measures have been adopted at a hospital in Okinawa to prevent vertical infections.Methods: We examined HTLV-I antibodies in all of the women (total 11, 506) who gave birth after 24 gestational weeks at a hospital on the Okinawa main island from January 1985 to December 1999.Results: The positive rate among all pregnant women was always higher than that among primipara alone. Both figures decreased over the period studied, but the primiparity rate (36-39%) did not change significantly. The percentage of HTLV-I positive primipara pregnant women among the HTLV-I positive total was close to the primiparity rate from 1985 to 1988, but it was considerably lower than the overall primiparity rate thereafter (22-26%).Conclusions: Preventive measures against HTLV-I infection did not contribute to the decrease in HTLV-I positive mothers before 1999 because these measures were adopted from 1985, and so there must be other reasons for the decrease in HTLV-I positive rate. Further studies on social factors and by year of birth are needed to identify factors influencing HTLV-carrier ratios among pregnant women.

Influence of cytokine and mannose binding protein gene polymorphisms on human t-cell leukemia virus type i (hTLV-i) provirus load in HTLV-I asymptomatic carriers

Human T-cell leukemia virus type I (HTLV-I) provirus load differs more than 100-fold among carriers and a high provirus load in the peripheral blood mononuclear cells (PBMCs) is regarded as a risk factor for both preleukemic states and inflammatory diseases including HTLV-I-associated myelopathy (HAM). We examined polymorphisms in the genes for tumor necrosis factor (TNF), TNF receptor type 1 and 2, lymphotoxin (LT)-α, interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and mannose binding protein (ManBP) in 143 HTLV-I carriers whether these polymorphisms affect the provirus load in the PBMCs of carriers. No significant association was observed between these polymorphisms and the provirus load. Homozygotes for a ManBP-variant allele, however, showed a tendency for the decreased number of provirus load. When combined, the data on the alleles of LT-α and MCP-1, HTLV-I carriers having high producer alleles of both genes showed a trend for increased provirus load. These data suggest that inflammation or an active immune response may induce an increased amount of HTLV-I–infected T cells, leading to a high provirus load.

Association between interleukin-6 gene polymorphism and human T-Cell leukemia virus type I associated myelopathy

We studied cytokine gene polymorphisms in the promoter region, including interleukin (IL)-6, IL-1β, and IL-10, in Japanese patients with human T-cell leukemia virus type I (HTLV-I) associated myelopathy (HAM) ( n = 65), asymptomatic HTLV-I carriers ( n = 143), and HTLV-I seronegative, normal controls ( n = 160). There was a significant difference between HAM patients and HTLV-I carriers in the distribution of IL-6 promoter polymorphism at position -634 (χ 2 = 9.90, p = 0.0071). The IL-6 genotype was also significantly different between HAM patients and normal controls (χ 2 = 11.53, p = 0.0033), while a similar distribution was observed in IL-1β and IL-10 polymorphisms among HAM patients, carriers, and normal controls. The results suggest that IL-6 gene region may contribute to susceptibility to HAM, and that aberrant cytokine productions could be involved in the development of HAM.

Transforming growth factor-beta enhances human T-cell leukemia virus type I infection.

Human T-cell leukemia virus type I (HTLV-I), the causative agent of adult T-cell leukemia/lymphoma, is transmitted vertically by breast milk and sexually by semen. The transforming growth factor-beta (TGF-beta), a pleiotropic cytokine that is abundant in breast milk and semen, facilitates replication of HTLV-I in lymphocytes derived from asymptomatic HTLV-I carriers and transmission to cord blood lymphocytes in vitro. Transient expression assays revealed that TGF-beta can transactivate HTLV-I long terminal repeat promoter. These results suggest that TGF-beta may play a role in replication and transmission of HTLV-I.

Impaired production of naive T lymphocytes in human T-cell leukemia virus type I–infected individuals: its implications in the immunodeficient state

AbstractOpportunistic infections frequently occur in patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I) carriers. However, the underlying mechanisms of such infections remain unknown. To clarify the mechanism of immunodeficiency in those infected with HTLV-I, this study analyzed the T-cell subsets in HTLV-I carriers and patients with HTLV-I–associated myelopathy/tropical spastic paraparesis and ATL using 3-color fluorescence with CD62L and CD45RA coexpression either with CD4+ or CD8+ T cells. The number of naive T lymphocytes was markedly suppressed in patients with ATL, particularly in those with acute form, compared with uninfected control individuals. The number of naive T cells was low in HTLV-I–infected individuals under 50 years old compared with uninfected individuals, whereas the number of memory T lymphocytes was greater in HTLV-I–infected individuals. Although the increase of memory T lymphocytes correlated with HTLV-I provirus loads, no relationship was found between naive T-cell counts and provirus loads. T-cell receptor rearrangement excision circles (TRECs), which are generated by DNA recombination during early T lymphopoiesis, were quantified to evaluate thymic function in HTLV-I–infected individuals. TREC levels were lower in HTLV-I–infected individuals than in uninfected individuals. In HTLV-I carriers less than 70 years old, an increase of Epstein-Barr virus DNA in peripheral blood mononuclear cells was observed in 6 of 16 (38%) examined, whereas it was detectable in only 1 of 11 uninfected controls. These results suggested that the low number of naive T lymphocytes was due to suppressed production of T lymphocytes in the thymus, which might account for immunodeficiency observed in HTLV-I–infected individuals.

A milk protein lactoferrin enhances human T cell leukemia virus type I and suppresses HIV-1 infection.

Human T cell leukemia virus type I (HTLV-I) and HIV-1, causative agents of adult T cell leukemia/lymphoma and AIDS, respectively, are transmitted vertically via breast milk. Here we demonstrate that lactoferrin, a milk protein that has a variety of antimicrobial and immunomodulatory activities, facilitates replication of HTLV-I in lymphocytes derived from asymptomatic HTLV-I carriers and transmission to cord blood lymphocytes in vitro. Transient expression assays revealed that lactoferrin can transactivate HTLV-I long terminal repeat promoter. In contrast, lactoferrin inhibits HIV-1 replication, at least in part, at the level of viral fusion/entry. These results suggest that lactoferrin may have different effects on vertical transmission of the two milk-borne retroviruses.

Ethnic segregation of HTLV‐I and HTLV‐II carriers among South American native Indians

To investigate the genetic background of human T-cell leukemia virus type I (HTLV-I) and II (HTLV-II) carriers among South American native Indians, we analyzed HLA DRB1*-DQB1* haplotypes of the virus carriers from Andes highlands and Orinoco lowlands by the PCR-RFLP genotyping method. It was revealed that the HTLV-I-carrying Andes natives had one of the 5 HLA haplotypes: DRB1*-DQB1* 0403-0302, 0802-0402, 0901-0303, 1406-0302 and 0407-0302, and that the Orinoco HTLV-II carriers had one of the 3 HLA haplotypes: DRB1*-DQB1* 1402-0301, 1602-0301 and 0404-0302. The HLA haplotypes of Andes HTLV-I carriers and Orinoco HTLV-II carriers were mutually exclusive. The haplotypes associated with HTLV-I carriers were commonly found among the Andes Indians and Japanese, which is the known HTLV-I endemic population, while the haplotypes associated with HTLV-II carriers were specifically found among the Orinoco Indians and North American Indians, among whom HTLV-II is endemic. These results suggested that HLA haplotypes might be ethnically segregated among South American natives and might be involved in the susceptibility to HTLV-I and HTLV-II infections.

Epidemiological features of HTLV-I and adult T cell leukemia.

Adult T-cell leukemia (ATL) patients and human T-cell leukemia virus type I (HTLV-I) carriers are clustered in limited groups in the world, especially among Japanese in Asia, Blacks in Central Africa, Melanesians in Papua New Guinea and Andeans in South America. The major transmission routes of HTLV-I under natural conditions are from mother-to-child through breast milk and from man-to-woman through semen. The whole life risk of ATL among persistent HTLV-I carriers is estimated at 2-6%. The detailed manifestation mechanism of ATL is not yet clarified; however, it is certain that HTLV-I infection in infancy is the main cause of ATL. Therefore, the prevention measure against mother-to-child transmission of HTLV-I is indispensable from a viewpoint of public health.