RANTES (regulated on activation normal T cell expressed and secreted) is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showed that peripheral blood mononuclear cells or CD4 ؉ lymphocytes obtained from different individuals had wide variations in their ability to secrete RANTES. These findings prompted us to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were two polymorphic positions, one of which was associated with reduced CD4 ؉ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This mutation, RANTES؊28G, occurred at an allele frequency of Ϸ17% in the non-HIV-1-infected Japanese population and exerted no inf luence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES؊28G mutation increases transcription of the RAN-TES gene. Taken together, these data suggest that the RANTES؊28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.The chemokine receptor CCR5 is an essential coreceptor for the cellular entry of R5 strains (macrophage tropic͞non-syncytium-inducing strains) of HIV-1 (1-6), which predominate in the early stages of infection (7). During the course of infection, variants called X4 strains (T cell-line tropic͞ syncytium-inducing strains) emerge (1, 8-11), which use CXCR4 as a coreceptor (12). In vitro replication of R5 strains can be blocked by the ligands for CCR5, macrophage inflammatory peptide-1␣ and -1␤, and RANTES (regulated on activation normal T cell expressed and secreted; refs. 13 and 14), whereas that of X4 strains can be blocked by the CXCR4 ligands stromal cell derived factor-1␣ and -1␤ (15, 16).Mutations in HIV-1 coreceptors and their natural ligand genes have been shown to modify HIV-1 transmission and disease progression. Individuals homozygous for a 32-nt deletion in the CCR5 coding region were resistant to HIV-1 infection (17, 18), whereas heterozygosity delays disease progression (19,20). A single V-to-I substitution in the first transmembrane segment of CCR2, a minor coreceptor for dual tropic R5X4 strains (3, 5), has a significant impact on disease progression but not on HIV-1 transmission in cohorts of seroconverters (21,22). Finally, homozygosity of a single G-to-A mutation in the 3Ј noncoding region of the stromal cell derived factor-1␤ gene also showed a disease-retarding effect (23), although later studies could not confirm this effect (24,25).Among three natural CCR5 ligands, RANTES showed the highest potency to suppress in vitro replication of R5 strains of HIV-1 (13). Phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) or CD4 ϩ enriched lymphocytes obtained from different...

Summary:Adult T cell leukemia/lymphoma (ATL) is a poor prognosis T cell malignancy. In order to improve the outcome, we employed allogeneic stem cell transplantation (allo-SCT) for ATL in 10 patients, nine of whom were from HLA-identical siblings and one from an unrelated donor. Conditioning regimens varied among the patients except that all received total body irradiation. The patients tolerated the regimens well with mild, if any toxicity, and engraftment occurred in all cases. Median leukemia-free survival after allo-SCT was 17.5+ months (range 3.7-34.4+). Six of the 10 patients developed acute GVHD (one case each with grade I, III or IV, and three cases with grade II) and three patients developed extensive chronic GVHD. Four patients died after allo-SCT during the study period from either acute GVHD (grade IV), pneumonitis, gastrointestinal bleeding or renal insufficiency. Two of the 10 cases with no symptoms of GVHD relapsed with clinical ATL. These results strongly suggest that allo-SCT may improve the survival in ATL if a controlled degree of GVHD develops. Bone Marrow Transplantation (2001) 27, 15-20.

HLA haplotypes of 27 patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) and 12 patients with adult T-cell leukemia/lymphoma (ATLL) were examined by analyzing HLA types of the patients and their family members. Either A11Bw54Cw1DR4DQw3, A24Bw54Cw1DR4DQ-, A24B7Cw7DR1DQw1, or A24Bw52Cw-DR2DQw1 and the related haplotypes were found in 70% of cases with HAM. None of these "HAM-associated" haplotypes was found in patients with ATLL. HLA haplotypes made up of HLA components of A26Bw62Cw3DR5DQw3 and one particular haplotype of Aw33B44Cw-DRw6DQw1 were associated with the ATLL haplotypes. These "ATLL-associated" haplotypes were also found in the patients with HAM who had no previous history of blood transfusion. The in vitro cultures of peripheral blood lymphocytes with HTLV-I virion antigens revealed that the response with HAM peripheral blood lymphocytes was remarkably higher than that with ATLL peripheral blood lymphocytes. Based on this HTLV-I-specific immune responsiveness, we can segregate the high responders in HAM (14 of 16 cases) and the low responders in ATLL (6 of 7 cases). The existence of high and low responders was also confirmed by the normal healthy individuals, whose responses were segregated with HAM-associated and ATLL-associated haplotypes. These results suggested that two ethnic groups in southern Kyushu may get the two different diseases, HAM and ATLL, because of their different immunogenetic backgrounds. The high immune response to HTLV-I seems to be an important genetic factor in the development of HAM.

In order to evaluate the protective role of the maternal antibody against mother-to-child transmission of HTLV-I, we followed a total of 780 children born to HTLV-I carrier mothers by investigating the level of anti-HTLV-I antibody transferred in utero, decline of the maternal antibody and seroconversion in post-natal life. The anti-HTLV-I antibody was positively detected within the first 3-6 months of life and declined at 6-12 months after birth in all children. After the maternal antibody declined, seroconversion occurred in some of the children following either breast feeding or bottle feeding. The seroconversion rates of short-term (less than or equal to 6 months) and long-term (greater than or equal to 7 months) breast feeders were 4.4% (4/90 cases) and 14.4% (20/139 cases), and the rate of bottle feeders was 5.7% (9/158 cases). Long-term breast feeding yielded more seroconverters than short-term breast feeding; 14.4% (20/139 cases) vs. 4.4% (4/90 cases), RR = 3.68, p = 0.018. The seroconversion rate of short-term breast feeders was nearly equal to that of bottle feeders; 4.4% (4/90 cases) vs. 5.7% (9/158 cases), RR = 0.770, p = 0.471. When neonatal lymphocytes were cultured with breast milk cells of HTLV-I carrier mothers, the in vitro infection of HTLV-I was inhibited by the addition of HTLV-I-seropositive cord-blood plasma. Our results suggest that the maternal antibody may inhibit HTLV-I infection by short-term breast feeding but not by long-term breast feeding after decline of the maternal antibody.

Genetic risk for adult T cell leukemia (ATL) has been implicated by ethnic and familial segregation of ATL patients from HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To clarify the genetic risk for ATL, we characterized HLA class I alleles of ATL patients and analyzed the anchor motifs of HTLV-1 peptides binding to HLA class I molecules, using 291 lines of anti-HTLV-1 CD8(+) cytotoxic T lymphocytes (CTLs) generated in vitro with a total of 165 synthetic peptides for HTLV-1 Tax and Env proteins. Allele frequencies of HLA-A*26, B*4002, B*4006, and B*4801 were significantly higher in ATL patients than in HAM/TSP patients and asymptomatic HTLV-1 carriers in southern Japan. CD8(+) CTL analysis revealed the HTLV-1 Tax peptide sequence to completely lack anchor motifs of peptides binding to HLA-A*26,B*4002, and B*4006 molecules but to possess one anchor for HLA-B*4801, while the HTLV-1 Env peptide sequence had many anchor motifs for HLA-A*26, B*4002, B*4006, and B*4801 molecules. Most ATL patients featured heterozygous HLA class I alleles composed of HLA-A*26, B*4002, B*4006, and B*4801, with a lower number of HTLV-1 Tax peptide anchor motifs and epitopes generating anti-HTLV-1 Tax CD8(+) CTLs than individuals possessing other HLA alleles. The relationship between Tax epitope and ATL incidence was verified by the significantly decreased number of HTLV-1 Tax epitopes in ATL patients compared with asymptomatic HTLV-1 carriers (p < 0.01) as well as late onset ATL patients (p < 0.001). These results indicate that HLA-A*26, B*4002, B*4006, and B*4801 alleles predispose to ATL because of the limited recognition of HTLV-1 Tax peptide anchor motifs and epitopes capable of generating anti-HTLV-1 Tax CD8(+) CTLs.

The worldwide geographic and ethnic clustering of patients with diseases related to human T-cell lymphotropic virus type I (HTLV-I) may be explained by the natural history of HTLV-I infection. The genetic characteristics of indigenous people in the Andes are similar to those of the Japanese, and HTLV-I is generally detected in both groups. To clarify the common origin of HTLV-I in Asia and the Andes, we analyzed HTLV-I provirus DNA from Andean mummies about 1,500 years old. Two of 104 mummy bone marrow specimens yielded a band of human beta-globin gene DNA 110 base pairs in length, and one of these two produced bands of HTLV-I-pX (open reading frame encoding p40x, p27x) and HTLV-I-LTR (long terminal repeat) gene DNA 159 base pairs and 157 base pairs in length, respectively. The nucleotide sequences of ancient HTLV-I-pX and HTLV-I-LTR clones isolated from mummy bone marrow were similar to those in contemporary Andeans and Japanese, although there was microheterogeneity in the sequences of some mummy DNA clones. This result provides evidence that HTLV-I was carried with ancient Mongoloids to the Andes before the Colonial era. Analysis of ancient HTLV-I sequences could be a useful tool for studying the history of human retroviral infection as well as human prehistoric migration.

Green tea polyphenols (TEA) are known to exhibit antioxidative activity as well as tumor-suppressing activity. In order to examine the tumor-suppressing activity of TEA against adult T-cell leukemia (ATL), we cultivated peripheral blood T lymphocytes of ATL patients (ATL PBLs), an HTLV-I-infected T-cell line (KODV) and healthy controls (normal PBLs) for 3 days in the presence of TEA and its main constituent, epigallocatechin-3-gallate (EGCg), to measure cell proliferation and apoptosis, and to quantitate mRNAs of HTLV-I pX and β β β β-actin genes of the cultured cells. Growth of ATL

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