Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.

Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations.

Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wild-type (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV's were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP-1 patterns with BL.

Risk of human T-lymphotropic virus type I-associated diseases in Jamaica with common HLA types.

Human T-lymphotropic virus-I (HTLV-I) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We postulated a higher disease risk for people with common human leukocyte antigen (HLA) types, due to a narrower immune response against viral or neoplastic antigens, compared to people with uncommon types. HLA class-I (A,B) and class-II (DRB1, DQB1) allele and haplotype frequencies in 56 ATL patients, 59 HAM/TSP patients and 190 population-based, asymptomatic HTLV-I-infected carriers were compared by logistic regression overall (score test) and with odds ratios (ORs) for common types (prevalence >50% of asymptomatic carriers) and by prevalence quartile. HTLV-I proviral load between asymptomatic carriers with common versus uncommon types was compared by t-test. ATL differed from asymptomatic carriers in overall DQB1 allele and class-I haplotype frequencies (p

Human leukocyte antigen concordance and the transmission risk via breast-feeding of human T cell lymphotropic virus type I.

OBJECTIVE: We examined the association between mother-to-child human T cell lymphotropic virus type I (HTLV-I) transmission and human leukocyte antigen (HLA) class I types. METHODS: In 1989, children born to HTLV-I-infected mothers in Jamaica were enrolled and prospectively evaluated for HTLV-I infection. HLA class I types in mothers and children were determined by DNA-based polymerase chain reaction methods. Associations between HLA class I types and transmission of HTLV-I were analyzed using proportional-hazards regression models adjusted for the duration of breast-feeding. Transmission risk in children still breast-feeding at 12 months was determined using actuarial methods. RESULTS: Of 162 children, 28 (17%) became infected. After Bonferroni's adjustment for multiple comparisons, the transmission risk was not influenced by any specific HLA class type or the A2 supertype. However, compared with children who shared 3 HLA class I types with their mothers (the minimum number possible), the transmission risk increased 1.8-fold with 4 shared types and 3.0-fold with 5 or 6 shared types (Ptrend = .039; 1.75-fold increase for each additional concordant HLA type). This association was independent of maternal HTLV-I proviral level, antibody titer, and household income. CONCLUSIONS: We found a significant dose-response relationship between HTLV-I transmission via breast-feeding and mother-child HLA class I type concordance. Immunological interactions between a child's cells and maternal cells may influence the risk of HTLV-I infection by breast-feeding, perhaps because antigens on maternal cells are seen by the child as being "self."

Genotypic characterization of Kaposi's sarcoma-associated herpesvirus in asymptomatic infected subjects from isolated populations.

Molecular epidemiological studies of Kaposi's sarcoma-associated herpesvirus (KSHV) have concentrated on characterization of viral strains in tumour biopsy samples from Kaposi's sarcoma (KS) patients, mostly obtained in the United States and Europe. Tumour biopsies are a convenient source of viral DNA, as they have a high viral load compared to peripheral blood. However, sequences obtained from biopsies may not be representative of viral strains in asymptomatic subjects and information on ethnicity is often not available. Here, a population-based approach has been used to study the molecular and seroepidemiology of KSHV in isolated populations in Ecuador and Botswana. Amerindians in Ecuador had a variable prevalence of KSHV and all strains characterized were of subtype E, based on K1 sequencing. All Amerindian strains had predominant (P)-type K15 alleles and had sequences in both T0.7 and ORF 75 that appeared to be characteristic of these strains. The prevalence of KSHV in two ethnic groups in Botswana was extremely high. K1 sequences from both Bantu and San subjects were mostly of subtypes B and A5, which are typical of African KSHV strains, but the sequence from one San subject did not cluster with any known subtype. Considerable heterogeneity was seen in the T0.7 and ORF 75 genes in the San subjects and one had a minor (M)-type K15 allele. The heterogeneity of the KSHV strains found in these subjects from Botswana contrasts with the homogeneity of KSHV strains in Amerindians, reflecting differences in the evolutionary history of these populations.

Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa

Seroprevalence of HHV-8 has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with HIV. Seroprevalence was found to be low in these countries. In contrast, the African countries of Ghana, Uganda and Zambia showed high seroprevalences in both healthy and HIV-infected populations. This suggests that human herpes virus-8 (HHV-8) may be either a recently introduced virus or one that has extremely low infectivity. Nasopharyngeal and oral carcinoma patients from Malaysia, Hong Kong and Sri Lanka who have very high EBV titres to show that only 3/82 (3.7 percent) have antibody to HHV-8, demonstrating that there is little, if any, cross-relativity between antibodies to these two gamma viruses. (AU)

Human T lymphotropic virus type I antibody patterns: evidence of difference by age and risk group

Detection of human T lymphotropic virus type I (HTLV-I) antibody was assessed on 368 sera from subjects with different clinical features and from different parts of the world. Enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay for purified p24 antibodies (p24-RIA) used as screening tests agreed in 88.7 percent of the sera. The results from 247 selected sera were compared with western blot (WB). WB was reactive in sera five to 25 times more dilute than the last positive ELISA or p24-RIA, but different WB batches varied in sensitivity. ELISA was more sensitive than p24-RIA, and p24-RIA was more specific than ELISA. Indeterminate WB interpretations were common (25.5 percent). Most seropositive intravenous drug abusers had unusually strong p24 bands by WB. Among healthy individuals, positive WB reactivity increased with age, whereas indeterminate reactivity declined (P=.034). Thus more sensitive and -specific HTLV-I antibody tests are needed. (AU)