Semiquantitative analysis of integrated genomes of human T-lymphotropic virus type I in asymptomatic virus carriers.

A semiquantitative estimation of human T-lymphotropic virus type I (HTLV-I) integration by peripheral blood mononuclear cells (PBMC) was performed. Genomic DNA samples derived from 134 HTLV-I carriers were subjected to 40 or 60 cycles of the polymerase chain reaction to amplify the pol region of HTLV-I. The HTLV-I genome was detected by dot hybridization using a 32P-labeled oligonucleotide probe for the pol region. The radioactivity of hybridized dot membranes was then counted with an RI Imaging System (Ambis Inc, San Diego, CA) and the HTLV-I genome dose was determined by comparison with standard curve for serially diluted HTLV-I genome-positive DNA. A wide range of variation of HTLV-I genome integration was observed. When the integrated genome dose was calculated as the number of HTLV-I copies per 100 PBMC, 7 carriers (5%) had more than 10 copies, 56 (42%) had 1 to 10 copies, 46 (34%) had 0.1 to 1 copy, and 24 (18%) had less than 0.1 copy. In one sample, the HTLV-I genome was undetectable, which may indicate that the integrated genome was present at less than 0.01 copies per 100 PBMC. Age- or sex-related variations in the distribution of individuals with different HTLV-I genome were rather limited. However, carriers with a high level of the HTLV-I genome were always more than 30 years old and were predominantly male (six of seven).     

Milk-borne transmission of HTLV-I from carrier mothers to their children

In order to clarify the natural transmission route of human T-cell leukemia virus type I (HTLV-I) from mother to child, we have followed two groups of children with ages of 1 to 3 years who were nourished either with HTLV-I-infected breast milk, or with non-infected milk from sero-positive, HTLV-I carrier mothers. Tests for the presence of antibody against HTLV-I revealed that 4 of 6 children in the former group developed HTLV-I infection, while only 1 of 14 children in the latter group became infected. The difference in HTLV-I infection rate for the children in the two groups was statistically significant (P less than 0.01 by chi-square). Furthermore, 2 of 4 elder siblings in the former group developed HTLV-I infection, whereas only one of 8 elder siblings in the latter group became infected. The overall rate of HTLV-I infection of breast-fed children born to HTLV-I-carrier mothers was 25% (8/32) by 3 years of age. Five of 6 mothers with HTLV-I-infected cells in the milk also possessed infected cells in their peripheral blood. Conversely 5 of 6 mothers without infected cells in the peripheral blood possessed no infected cells in their breast milk, suggesting that HTLV-I-infected cells in the peripheral blood can enter the breast milk. None of the 8 breast-fed children born to carrier mothers whose peripheral blood and breast milk-borne cells were negative, developed HTLV-I infection, suggesting that HTLV-I transmission from mother to child is dependent upon the number of HTLV-I-infected cells in carrier mothers.     

Survey of anti-human T-cell leukemia virus type I antibody in family members of patients with adult T-cell leukemia

To evaluate the intrafamilial clustering of HTLV-I, we examined the sera or plasma of 296 healthy family members of patients with adult T-cell leukemia (ATL) for anti-HTLV-I antibodies. Of 296 subjects, 132 (44.6%) had anti-HTLV-I antibodies. Fifty-nine (41.0%) out of 144 males and 73 (48.0%) out of 152 females were seropositive. The positive rates of antibody to HTLV-I increased with age, especially between the 30-39 and the 40-49 age groups. Five out of 6 fathers, 3 out of 4 mothers, 31 (60.8%) out of 51 spouses, 40 (63.5%) out of 63 siblings and 46 (33.8%) out of 136 children of patients with ATL had anti-HTLV-I antibodies. Of 74 children with an ATL father, 14 (18.9%) were seropositive, while 32 (51.6%) out of 63 children with an ATL mother were seropositive. This difference was statistically significant (P less than 0.001). Of those children with an ATL father, 12 (26.1%) out of 46 whose mothers were HTLV-I carriers had antibodies to HTLV-I. In contrast, none of the 13 children whose mothers were not carriers were seropositive. These results supported the hypothesis that the mother-to-child transmission is one of the most important modes of HTLV-I transmission. In wives of male patients with ATL, the positive rate of antibody to HTLV-I was 65.6% (21/32), and in husbands of female patients, it was 52.6% (10/19). The high positive rate of antibody to HTLV-I not only in wives of male patients but also in husbands of female patients suggests that either HTLV-I is more frequently transmitted from wives to their husbands than we had originally expected, or that ATL may develop even in wives who acquire HTLV-I from their husbands after marriage.     

Frequency of eosinophilia in adult T-cell leukemia/lymphoma.

Cases of adult T-cell leukemia/lymphoma (ATLL) display several peculiar clinical features, including skin rash, hypercalcemia, and an increase in the absolute neutrophil count. The patients rarely have pronounced eosinophilia. In this study, the eosinophilia observed in lymphoproliferative disorders of 62 patients with ATLL, 27 with T-cell lymphoma (TL), and 19 with B-cell lymphoma (BL) was investigated. The incidence of eosinophilia (greater than or equal to 570/microliters) was higher in patients with ATLL than in patients with TL or BL. Thirteen patients with ATLL (21.0%), 3 with TL (11.1%), and 2 with BL (10.5%) had eosinophilia. Of these patients, three with ATLL and one with TL who had a pathologic diagnosis of immunoblastic lymphadenopathy (IBL) showed pronounced eosinophilia up to 10,934/microliters. Because the number of eosinophils in the peripheral blood of these patients correlated both with the number of ATLL cells and the degree of lymphadenopathy and because this fluctuated with chemotherapy, it seems likely that the secretion of some lymphokines by the lymphoma cells is responsible for the eosinophilia.     

Oral infection of a common marmoset with human T-cell leukemia virus type-I (HTLV-I) by inoculating fresh human milk of HTLV-I carrier mothers

To obtain definitive evidence that milk-borne infection plays a critical role in the endemy or mother-to-child transmission of human T-cell leukemia virus type-I (HTLV-I), we inoculated concentrated fresh human milk cells obtained from HTLV-I carrier mothers into the oral cavity of a common marmoset (Callithrix jacchus). Twenty-eight milk samples were collected (5-10 ml each) from 17 carrier mothers in the first week after delivery. Cells in the milk were centrifuged down and resuspended in 1/10 vol of the milk fluid. The concentrated cell suspensions were successively inoculated into the oral cavity of a common marmoset. The marmoset was found to be seroconverted by indirect immunofluorescence assay at 2.5 months after the first inoculation of the milk (3.5 X 10(8) cells in total), and was later confirmed to be infected with HTLV-I by the detection of viral antigen expression in short-term cultures of its peripheral blood T-lymphocytes. The results strongly support the working hypothesis that milk-borne infection plays a significant role in the mother-to-child transmission of HTLV-I.     

Familial disposition of adult T-cell leukemia and lymphoma

Sixteen families, each with two or more cases of adult T-cell leukemia or lymphoma were found in the Nagasaki district. Eight of the families had a parent with lymphoma. In the other eight families siblings were involved. Four families with sibling cases are presented in detail. Antibody titres to adult T-cell leukemia associated antigen (ATLA) in cases of ATL, CTL, T-CLL, and pre-ATL cases in Nagasaki were all positive. Of the non-leukemic T-cell malignant lymphoma 62.5 per cent were positive for antibody. The positive rate in healthy spouses and siblings of ATLL patients for ATLA antibody was high (67.5 per cent and 40 per cent respectively). The possibility of ATLV infection through spouses or from mother to child and the meaning of the high familial incidence of ATLL is discussed.     

Survey of Anti-human T-Cell Leukemia Virus Type I Antibody in Family Members of Patients with Adult T-Cell Leukemia

To evaluate the intrafamilial clustering of HTLV-I, we examined the sera or plasma of 296 healthy family members of patients with adult T-cell leukemia (ATL) for anti-HTLV-I antibodies. Of 296 subjects, 132 (44.6%) had anti-HTLV-I antibodies. Fifty-nine (41.0%) out of 144 males and 73 (48.0%) out of 152 females were seropositive. The positive rates of antibody to HTLV-I increased with age, especially between the 30–39 and the 40–49 age groups. Five out of 6 fathers, 3 out of 4 mothers, 31 (60.8%) out of 51 spouses, 40 (63.5%) out of 63 siblings and 46 (33.8%) out of 136 children of patients with ATL had anti-HTLV-I antibodies. Of 74 children with an ATL father, 14 (18.9%) were seropositive, while 32 (51.6%) out ot 63 children with an ATL mother were seropositive. This difference was statistically significant ( P <0.001). Of those children with an ATL father, 12 (26.1%) out of 46 whose mothers were HTLV-I carriers had antibodies to HTLV-I. In contrast, none of the 13 children whose mothers were not carriers were seropositive. These results supported the hypothesis that the mother-to-child transmission is one of the most important modes of HTLV-I transmission. In wives of male patients with ATL, the positive rate of antibody to HTLV-I was 65.6% (21/32), and in husbands of female patients, it was 52.6% (10/19). The high positive rate of antibody to HTLV-I not only in wives of male patients but also in husbands of female patients suggests that either HTLV-I is more frequently transmitted from wives to their husbands than we had originally expected, or that ATL may develop even in wives who acquire HTLV-I from their husbands after marriage.