Human T-cell lymphotropic virus type I infection and disease in the Pacific basin.

Human T-cell lymphotropic virus type I (HTLV-I), the cause of adult T-cell leukemia/lymphoma (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is widespread in the Pacific basin. Modes of virus transmission include blood transfusion (and intravenous drug use), breast milk, and sexual intercourse. High prevalences of HTLV-I infection and disease occur among the inhabitants of southwestern Japan and among first- and second-generation (issei and nisei) Japanese-Americans in the Hawaiian Islands. Other Pacific populations with high prevalences of HTLV-I infection include several remote groups in West New Guinea, Papua New Guinea, the Solomon Islands, and Vanuatu, which have had no contact with Japanese or Africans. By contrast, Micronesian and Polynesian populations, even those with prolonged contact with Japanese, exhibit low prevalences or no evidence of HTLV-I infection. Low prevalences of infection are also found in Australia, except among some aboriginal populations. Changing patterns of HTLV-I infection and disease are no better exemplified than in Japan, where striking reductions in transfusion-acquired infection and subsequent development of HAM/TSP have followed the institution of nationwide screening of blood donors for HTLV-I infection. Furthermore, virus transmission from mother to infant by means of infected breast milk has been markedly curtailed in HTLV-I-hyperendemic regions in Japan by interrupting the practice of breast feeding by HTLV-I-infected mothers. The next frontier of HTLV-I research is in Melanesia, where highly divergent sequence variants of HTLV-I have been discovered.     

Genetic and phylogenetic analyses of human T-cell lymphotropic virus type I variants from Melanesians with an without spastic myelopathy

Molecular variants of human T-cell lymphotropic virus type I (HTLV-I) have been isolated recently from lifelong residents of remote Melanesian populations, including a Solomon Islander with tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) or HTLV-I myeloneuropathy. To clarify the genetic heterogeneity and molecular epidemiology of disease-associated strains of HTLV-I, we enzymatically amplified, then directly sequenced representative regions of thegag, pol, env, andpX genes of HTLV-I strains from Melanesians with and without TSP/HAM, and aligned and compared these sequences with those of HTLV-I strains from patients with TSP/HAM or adult T-cell leukemia/lymphoma and from asymptomatic carriers from widely separated and culturally disparate populations. Overall, the HTLV-I variant from the Solomon Islander with TSP/HAM, like HTLV-I strains from asymptomatically infected Melanesians, diverged by approx 7% from cosmopolitan HTLV-I strain. No disease-specific viral sequences were found. Gene phylogenies, as determined by the unweighted pair-goup method of assortment and by the maximum parsimony method, indicated that the Melanesian and cosmopolitan strains of HTLV-I have evolved along separate geographically dependent lineages, one comprised of HTLV-I strains from Papua New Guinea and the Solomon Islands, and the other composed of virus strains from Japan, India, the Caribbean, Polynesia, the Americas, and Africa. The total absence of nonhuman primates in Papua New Guinea and the Solomon Islands precludes any possibility that the Melanesian HTLV-I strains have evolved recently from the simian homolog of HTLV-I.     

Functional compensation by insular scavengers: the relative contributions of vertebrates and invertebrates vary among islands

When the extinction of some species results in loss of ecosystem functions, other species may be able to compensate for this loss. Functional compensation has recently been observed on islands where species are likely to become extinct; however, few studies have analysed functional compensation by scavengers in insular environments. Here, we investigated the ecosystem functions of vertebrate and invertebrate scavengers on Honshu, the main island of Japan, and offshore islands (four of the Oki Islands). The Oki Islands lack several native vertebrate scavengers (raccoon dogs, boars, martens, and foxes) that are abundant on Honshu. We experimentally placed mouse carcasses on the forest floors of Honshu (12 sites) and the Oki Islands (7 sites on Dōgo, 4 sites on Nishinoshima, 4 sites on Nakanoshima, and 3 sites on Chiburijima) in September–October 2014 and 2015. Nearly all of the mouse carcasses (95–100%) placed on the forest floor disappeared within 1 week. However, the relative importance of vertebrate and invertebrate scavengers varied among islands. Vertebrate and invertebrate scavengers contributed equally on Honshu (carcass removal by vertebrates, 47%), whereas vertebrate scavengers rarely contributed to carcass removal on three of the Oki Islands (carcass removal by vertebrates: 17% on Dōgo, 30% on Nishinoshima, and 5% on Nakanoshima). Consequently, invertebrate scavengers (Nicrophorus burying beetles) functionally compensated for the low species diversity of vertebrate scavengers on the three islands (carcass burial by Nicrophorus beetles, 65–95%). However, on the small island of Chiburijima, introduced raccoon dogs contributed to nearly all of the removals (93%), suggesting that introduced scavengers can compensate for the functional reduction. This functional compensation by scavengers may help stabilise the functions and/or services of scavengers in island environments.     

Seroepidemiologic study of adult T-cell leukemia virus (ATLV) and hepatitis B virus infection in Okinawa, Japan

A total of 2,283 serum samples were collected from healthy subjects in three islands of the Yaeyama district of Okinawa, Japan. These sera were tested for the presence of hepatitis B surface antigen (HBsAg), for antibody to hepatitis B core antigen (anti-HBc), and for antibody to adult T-cell leukemia-associated antigen (anti-ATLA). Correlation between hepatitis B virus infection and adult T-cell leukemia virus (ATLV) infection was determined by using the prevalence rates for three virus markers. Overall prevalence of HBsAg, anti-HBc and anti-ATLA was 6.5%, 57.4%, and 17.9%, respectively. Age-specific prevalence of anti-HBc and anti-ATLA increased with age, but that of HBsAg did not. Sex-specific prevalence of HBsAg was significantly higher in males than in females, but that of anti-ATLA was significantly higher in females than in males. Statistical analysis revealed that prevalence of anti-ATLA was significantly higher in HBsAg-positive persons and HBsAg-negative/anti-HBc-positive persons than in those negative for HBsAg and anti-HBc. These data suggest that hepatitis B virus-infected persons have a significantly higher chance of adult T-cell leukemia virus infection than those without hepatitis B virus infection in the area studied.     

Complete nucleotide sequence of a highly divergent human T-cell leukemia (lymphotropic) virus type I (HTLV-I) variant from melanesia: genetic and phylogenetic relationship to HTLV-I strains from other geographical regions.

The high prevalences of antibodies against human T-cell leukemia (lymphotropic) virus type I (HTLV-I) reported for remote populations in Papua New Guinea and the Solomon Islands and for some aboriginal populations in Australia have been verified by virus isolation. Limited genetic analysis of the transmembrane portion (gp21) of the envelope gene of these viruses indicates the existence of highly divergent HTLV-I strains in Melanesia. Here, we report the complete nucleotide sequence of an HTLV-I isolate (designated HTLV-IMEL5) from the Solomon Islands. The overall nucleotide divergence of HTLV-IMEL5 from the prototype HTLV-IATK was approximately 8.5%. The degree of variability in the amino acid sequences of structural genes ranged between 3 and 11% and was higher (8.5 to 25%) for the regulatory (tax and rex) genes and the other genes encoded by the pX region. Since HTLV-IMEL5 was as distantly related to HTLV-II as to the other known HTLV-I strains, it could not have arisen from a reocmbinational event involving HTLV-II but rather might be an example of independent viral evolution in this remote population. These data provide important insights and raise new questions about the origin and global dissemination of HTLV-I.     

Tax mutation associated with tropical spastic paraparesis/human T-cell leukemia virus type I-associated myelopathy.

Tumaco, Colombia, is an area with elevated rates of tropical spastic paraparesis/human T-cell leukemia virus type I (HTLV-I)-associated myelopathy (TSP/HAM). We have identified a mutation in nucleotide 7959 of the tax gene of 14 Tumaco HTLV-I isolates (14 positive of 14 tested) that was present in 5 of 14 (35%) TSP/HAM patients from Japan and in 8 of 11 (72%) TSP/HAM patients from other geographic locations. In contrast, this mutation was found in only 2 of 21 (9.5%) HTLV-I-infected subjects outside of Tumaco who did not have TSP/HAM. tax clones with nucleotide mutations including one at nucleotide 7959 showed a greater ability to transactivate the HTLV-I U3 promoter. However, this effect was not observed when two clones that differed only in nucleotide 7959 were compared. These results suggest that HTLV-I-infected individuals carrying isolates with this tax mutation are at higher risk for developing TSP/HAM.     

Strongyloidiasis associated with human T-cell lymphotropic virus type I infection in a nonendemic area.

Concomitant strongyloidiasis and human T-cell lymphotropic virus type I (HTLV-I) infection has been reported from areas in Japan where both organisms are endemic. We present four cases of concomitant infection with these organisms from an area that is not endemic for Strongyloides stercoralis. Three of the four patients had adult T-cell leukemia, an aggressive neoplasm resulting from HTLV-I infection, while the other was an asymptomatic carrier of HTLV-I. Three of the patients had spent their childhoods in an endemic location for both organisms, suggesting an initial infection at that time. Three patients were symptomatic from their parasitism. We conclude that strongyloidiasis may be found in nonendemic locations in patients with either adult T-cell leukemia or an asymptomatic HTLV-I carrier state. Whether infestation with this parasite contributes to the leukemogenesis of HTLV-I, as postulated by others, cannot at this time be determined.     

Genetic heterogeneity in human T-cell leukemia/lymphoma virus type II.

DNA from the peripheral blood mononuclear cells of 17 different individuals infected with human T-cell lymphoma/leukemia virus type II (HTLV-II) was successfully amplified by the polymerase chain reaction (PCR) with the primer pair SK110/SK111. This primer pair is conserved among the pol genes of all primate T-cell lymphoma viruses (PTLV) and flanks a 140-bp fragment of DNA which, when used in comparative analyses, reflects the relative degree of diversity among PTLV genomes. Cloning, sequencing, and phylogenetic comparisons of these amplified 140-bp pol fragments indicated that there are at least two distinct genetic substrains of HTLV-II in the Western Hemisphere. These data were confirmed for selected isolates by performing PCR, cloning, and sequencing with to 10 additional primer pair-probe sets specific for different regions throughout the PTLV genome. HTLV-II isolates from Seminole, Guaymi, and Tobas Indians belong in the new substrain of HTLV-II, while the prototype MoT isolate defines the original substrain. There was greater diversity among HTLV-II New World strains than among HTLV-I New World strains. In fact, the heterogeneity among HTLV-II strains from the Western Hemisphere was similar to that observed in HTLV-I and simian T-cell lymphoma/leukemia virus type I isolates from around the world, including Japan, Africa, and Papua New Guinea. Given these geographic and anthropological considerations and assuming similar mutation rates and selective forces among the PTLV, these data suggest either that HTLV-II has existed for a long time in the indigenous Amerindian population or that HTLV-II isolates introduced into the New World were more heterogeneous than the HTLV-I strains introduced into the New World.     

Systematic Relationships of Hynobius okiensis among Japanese Salamanders (Amphibia: Caudata)

We conducted an electrophoretic survey to examine systematic relationships of a lotic-breeding salamander Hynobius okiensis endemic to Dogo Island of the Oki Islands, Japan, with several lentic and lotic-breeding Japanese species. Genetically H. okiensis with 2n=56 chromosomes was closer to the lentic-breeding H. nebulosus group (H. nebulosus and H. dunni) with the same chromosome number than to the lotic-breeding H. naevius group (H. naevius and H. kimurae) and H. boulengeri with 58 chromosomes. Chromosome number reduction from 58 to 56, possibly accompanied with a change in breeding environment from streams to still waters, is estimated to have first occurred in the nebulosus group of Hynobius. A reversal only in breeding habits then seems to have followed in steep, montane environments of the small island of Dogo, resulting in the speciation of H. okiensis.     

Gross anatomy of Watase's shrew, Crocidura horsfieldi watasei

The Watase's shrew (Crocidura horsfieldi watasei) which is a native in the Nansei Islands in Japan, is one of the smallest mammalian species with 5-8 g of the body weight. Both males and females were caught in the field of the Amami Islands, and their internal organs in the thoracic and abdominal cavities were examined under the dissecting microscope and by the serial cross sections method. In comparison with the musk shrew belonging to the same subfamily Crocidurinae, the following features were basically similar; very short intestine in comparison with the body length, the absence of cecum, and the structure of the genital organs. Besides, the following were different; the small sized body, the small sized spleen compared with the body weight, and the cardiac glands limited in the end of the esophagus.     

Chipping at large, potent human T-cell leukemia virus type 1 protease inhibitors to uncover smaller, equipotent inhibitors

The human T-cell leukemia virus type 1 (HTLV-I) causes adult T-cell leukemia and several severe chronic diseases. HTLV-I protease (PR) inhibition stops the propagation of the virus. Herein, truncation studies were performed on potent octapeptidic HTLV-I PR inhibitor KNI-10161 to derive small hexapeptide KNI-10127 with some loss in activity. After performing residue-substitution studies on compound KNI-10127, HTLV-I PR inhibitory activity was recovered in inhibitor KNI-10166.     

Human T-lymphotropic virus type I (HTLV-I) and tropical spastic paraparesis or HTLV-I-associated myelopathy in Hawaii.

Tropical spastic paraparesis or human T-lymphotropic virus type I (HTLV-I)-associated myelopathy is a degenerative encephalomyelopathy with pyramidal tract dysfunction affecting the lower extremities. It is associated with HTLV-I infection and found primarily in the Caribbean region and in southwestern Japan. Five cases of tropical spastic paraparesis (or HTLV-I-associated myelopathy) in Hawaii are reported. All five patients were born in Hawaii; four are women. Each of the patients has parents who were from HTLV-I-endemic areas of Japan. Two of these patients had serum antibodies to HTLV-I. Five of six of the spouses and children of the seropositive patients were also seropositive. Viral cultures of lymphocytes from both seropositive patients and two of the three seropositive children were positive for HTLV-I. None of the five patients had a history of antecedent blood transfusion, multiple sexual partners, or intravenous drug use. There is no evidence of adult T-cell leukemia or lymphoma in any of the patients or their families. Given the increasing seroprevalence of HTLV-I in the United States, clinicians need to be alert to new cases of this disorder.     

Human T-lymphotropic virus type I seroprevalence among Japanese Americans.

The epidemiology of human T-lymphotropic virus type I (HTLV-I) infection is not well defined in Japanese Americans. This impairs using approaches that could reduce viral transmission and monitor carriers for the disease. Using enzyme-linked immunosorbent assay and p21e recombinant Western blot testing, HTLV-I antibody was measured in unlinked samples from Japanese-American patients at 4 physicians'' offices in San Francisco, California. Of 442 patients, 4 (0.9%; 95% confidence interval 0.25%, 2.3%) were confirmed seropositive, all with an HTLV-I rather than an HTLV-II pattern on Western blot. Seroprevalence was highest among the issei or immigrant generation (3/230 or 1.3%) compared with the second-generation nisei (1/191 or 0.5%) or third-generation sansei (0 of 17). Prevalence did not differ by age or sex, although the number of positive subjects in each subgroup was small. Of 88 patients with familial origins in endemic areas of southern Japan, none were seropositive. In this sample of Japanese Americans, HTLV-I seroprevalence was lower than in residents of endemic southern Japan but higher than among American blood donors. The prevalence was most similar to that in nonendemic areas of Japan. The public health implications of HTLV-I infection among Japanese Americans are discussed.     

Immunological risks of adult T-cell leukemia at primary HTLV-I infection

A small percentage of human T-cell leukemia virus type-I (HTLV-I)-infected individuals develop adult T-cell leukemia (ATL). In animal experiments, inoculation of HTLV-I via the oral route, which is the main route of mother-to-child viral transmission in humans as a result of breastfeeding, induced host HTLV-I-specific T-cell unresponsiveness and resulted in increased viral load. This strongly suggested that the known epidemiological risk factors for ATL (i.e. vertical HTLV-I infection and elevated viral load) are linked by an insufficient HTLV-I-specific T-cell response. Recent findings on the anti-tumor effects of Tax-targeted vaccination in rats and the reactivation of Tax-specific T cells in ATL patients as a result of hematopoietic stem cell transplantation imply promising immunological approaches for the prophylaxis and therapy of ATL.     

Valproic acid and HIV-1 latency: beyond the sound bite

In 1977, Takatsuki and co-workers described in Japan a human malignant disease termed adult T-cell leukemia (ATL). Three years later, in 1980, Gallo and colleagues reported the identification of the first human retrovirus, human T-cell leukemia virus type I (HTLV-I), in a patient with cutaneous T-cell lymphoma. This month, Retrovirology commemorates these two land mark findings by publishing separate personal recollections by Takatsuki and Gallo respectively on the discovery of ATL and HTLV.     

Lack of tax diversity for tropical spastic paraparesis/human T-cell lymphotropic virus type 1 (HTLV-I) associated myelopathy development in HTLV-I-infected subjects in São Paulo, Brazil

The product of human T-cell lymphotropic virus type 1 (HTLV-1) tax gene has a transactivating effect of the viral and cellular gene expression. Genetic variations in this gene have been correlated with differences in clinical outcomes. Based upon its diversity, two closely related substrains, namely tax A and tax B, have been described. The tax A substrain has been found at a higher frequency among human T-cell leukemia virus type 1 (TSP/HAM) patients than among healthy HTLV-I-infected asymptomatic subjects in Japan. In this study, we determined the distribution of tax substrains in HTLV-I-infected subjects in the city of S?o Paulo, Brazil. Using the ACCII restriction enzyme site, we detected only tax A substrain from 48 TSP/HAM patients and 28 healthy HTLV-I carriers. The sequenced tax genes from nine TSP/HAM patients and five asymptomatic HTLV-I carriers showed a similar pattern of mutation, which characterizes tax A. Our results indicate that HTLV-I tax subtypes have no significant influences on TSP/HAM disease progression. Furthermore, monophyletic introduction of HTLV-I to Brazil probably occurred during the African slave trade many years ago.     

Human T-cell lymphotropic virus type I and adult T-cell leukemia/lymphoma outside Japan and the Caribbean Basin

Ninety-six patients with the diagnosis of adult T-cell leukemia/lymphoma (ATLL) were identified in countries outside Japan and the Caribbean Basin. Seventy-four of these patients were initially diagnosed in the United States; 25 of 52 patients whose places of birth were known had been born in the United States. The detection of 14 patients born in the southeastern United States, all black, indicates a group deserving particular attention for studies of human T-cell lymphotropic virus type I (HTLV-I), a suspected etiologic agent in most cases of ATLL. Although geographic clustering of ATLL in areas endemic for HTLV-I, particularly southwest Japan and the Caribbean Basin, is a dramatic feature of this disease, a review of the literature indicates that HTLV-I-associated ATLL probably occurs sporadically in a much wider distribution, the disease being diagnosed in native-born African, Chinese, European, and Latin American patients. A registry for ATLL cases is suggested, to assist in the identification of risk factors for this disease and, at the same time, improve case definitions and early diagnosis.     

Prevalence of antibodies interactive with HTLV-I antigens in selected Solomon Islands populations

Serum samples obtained in 1986 from healthy individuals in three distinct Solomon Islands populations were screened for antibodies to human lymphotropic virus type I (HTLV-I). One of the populations tested lives on the remote Polynesian outlier atoll, Ontong Java. The other two groups, the Baegu and the Lau, are Melanesians living on Malaita, the most populous of the larger Solomon Islands. Eighty-eight of a total of 601 (14.6%) sera tested were repeatably reactive in an enzyme-linked immunosorbent assay (ELISA) that uses as antigen a lysate of HTLV-I viral particles. The prevalence of antibodies interactive with HTLV-I viral particles. The prevalence of antibodies interactive with HTLV-I antigens varied among the three groups, ranging from 8.5% (16/188) in the Baegu, through 13% (7/54) in the Lau, to 18.1% (65/359) among the Ontong Java population. The specificity of the screening ELISA was confirmed by protein immunoblot. No serum samples were obtained from children under 9 years of age. Although 121 of the 601 sera came from children between the ages of 9 and 19, none of these were reactive in the HTLV-I ELISA. Starting in the third decade, the prevalence of HTLV-I seropositivity increased with age, from 8.8% (10/113) between the ages of 20 and 29 to a peak of 25.9% (15/58) and 25% (15/60) in the sixth and seventh decade, respectively. This age-specific prevalence pattern is strikingly similar to that which is seen in populations where HTLV-I infection is endemic.     

In vivo genomic variability of human T-cell leukemia virus type I depends more upon geography than upon pathologies.

To investigate the geography- and disease-associated genomic variation of human T-cell leukemia virus type I (HTLV-I), we studied ex vivo DNA from peripheral blood lymphocytes from nine patients by polymerase chain reaction and direct DNA sequencing. For each viral strain, 1,917 bp was sequenced, including parts of the long terminal repeat, the env gene, and the px II, px III, and px IV coding frames of the px region. The number of genomic variations observed in the U3 region of the long terminal repeat was higher than that seen in the env and px genes. Very few mutations were present in the px II and px III genes. In contrast, the px IV open reading frame exhibited numerous single point mutations. While no specific mutation could be linked to any pathology (adult T-cell leukemia/lymphoma or tropical spastic paraparesis/HTLV-I-associated myelopathy), variations among HTLV-I isolates from different geographic areas (Ivory Coast, Caribbean, and Japan) existed. The Ivory Coast HTLV-I appeared to represent a group by itself.