Haplotype-dependent HLA susceptibility to nasopharyngeal carcinoma in a Southern Chinese population.

We have conducted a comprehensive case-control study of a nasopharyngeal carcinoma (NPC) population cohort from Guangxi Province of Southern China, a region with one of the highest NPC incidences on record. A total of 1407 individuals including NPC patients, healthy controls, and their adult children were examined for the human leukocyte antigen (HLA) association, which is so far the largest NPC cohort reported for such studies. Stratified analysis performed in this study clearly demonstrated that while NPC protection is associated with independent HLA alleles, most NPC susceptibility is strictly associated with HLA haplotypes. Our study also detected for the first time that A(*)0206, a unique A2 subtype to South and Southeast Asia is also associated with a high risk for NPC. HLA-A(*)0206, HLA-B(*)3802 alleles plus the A(*)0207-B(*)4601 and A(*)3303-B(*)5801 haplotypes conferred high risk for NPC showing a combined odds ratio (OR) of 2.6 (P<0.0001). HLA alleles that associate with low risk for NPC include HLA-A(*)1101, B(*)27, and B(*)55 with a combined OR of 0.42 (P<0.0001). The overall high frequency of NPC-susceptible HLA factors in the Guangxi population is likely to have contributed to the high-NPC incidence in this region.

The causes of cancer in France.

BACKGROUND: While external factors are responsible for many human cancers, precise estimates of the contribution of known carcinogens to the cancer burden in a given population have been scarce. METHODS: We estimated the proportion of cancer deaths which occurred in France in 2000 attributable to known risk factors, based on data on frequency of exposure around 1985. RESULTS: In 2000, tobacco smoking was responsible for 23.9% of cancer deaths (33.4% in men and 9.6% in women), alcohol drinking for 6.9% (9.4% in men and 3.0% in women) and chronic infections for 3.7%. Occupation is responsible for 3.7% of cancer deaths in men; lack of physical activity, overweight/obesity and use of exogenous hormones are responsible for 2%-3% of cancer deaths in women. Other risk factors, including pollutants, are responsible for <1% of cancer deaths. Thus, known risk factors explain 35.0% of cancer deaths, and 15.0% among never smokers. CONCLUSIONS: While cancer mortality is decreasing in France, known risk factors of cancer explain only a minority of cancers, with a predominant role of tobacco smoking.

Ethical issues in research on control of the HIV/AIDS epidemic: report from a workshop of the world federation of scientists, Erice, Sicily, Italy, 22-24 August 2003.

In research on control of the HIV/AIDS epidemic there are many ethical issues to be considered. The problem of personal autonomy versus the interest of society to prevent the spread of the disease in various settings makes it difficult to follow the regulations of the Declaration of Helsinki in all respects. This is particularly clear in the evaluation of trials aimed at preventing mother-to-child transmission of HIV. The interest of the child does not always conform to the policy of avoiding stigmatization of the mother. Programmes for the implementation of antiretroviral therapy and vaccine trials may differ in countries with different mean incomes of the inhabitants, and are also influenced by local patterns. For this reason, the Declaration of Helsinki should be changed in such a way that it conforms with the ways in which it may be possible to combat such a disastrous epidemic as that caused by HIV.

Prospects of vaccination as a means of preventing mother-to-child transmission of HIV-I.

Although short-course antiretroviral therapy is efficient in reducing mother-to-child transmission (MTCT) of HIV-1, it does not prevent transmission during the breastfeeding period. There is therefore an urgent need to test various approaches, including HIV-1 vaccination, to try to prevent postnatal transmission of HIV-1 in breastfeeding populations in developing countries.

[Preliminary study of human Herpesvirus type 8 infection in pregnant women in Dakar (Senegal)]. / Etude préliminaire de l'infection à Herpesvirus humain type 8 chez les femmes enceintes à Dakar (Sénégal).

HHV8 was discovered in 1994 and few studies on this virus have been conducted in Africa. The virus is related to Kaposi sarcoma, an opportunistic affection occurring during HIV infection. No studies have been carried out on this subject in Senegal, a country known for its low KS prevalence even among people living with HIV/AIDS. Thus it will be interesting to explore this field. The aim of our study has been first, to demonstrate the presence of HHV8; second, to evaluate sero-prevalence of the infection in Senegal and third, to determine the specificities of HHV8 infection in our country. We performed our study on 407 pregnant women whose average age was 29.24 years, the majority of whom were Senegalese. HIV serology was done by dot blot for the screening and western blot for the confirmation. For the diagnosis of HHV8 infection, we used the indirect immunofluorescence kit of ABI. HIV infection was low among this study population; 0.5% and no HIV1 infection was mentioned. Among the 407 women, 58 or 14.3% were HHV8 positive and there was no HHV8/HIVco-infection. Regarding marital status, no significant difference was found between HHV8 positive and HHV8 negative among unmarried, monogamous or polygamous women. However, women having had 4 to 5 children were more likely to test positive for HHV8. The difference is significant and a relationship has been established with a p value of 0.02. Regarding pregnancy, HHV8 infection is more closely related to abortion: 17.2% of women who had aborted were HHV8 positive versus 4.9% seronegative. The odds ratio calculation shows a strong correlation with a p value of 0.01. No correlation was found between HHV8 infection of the mother and neonate mortality or Apgar score. However, a relationship did show up between HHV8 infection of the mother and low birth weight. 29.2% of seropositive women had had a child with a birth weight under 2600 g whereas only 16.3% of seronegative women had had babies with low birth weight. We determined that HHV8 is indeed present in Senegal. Further studies should focus on transmission routes as well as the molecular epidemiology of this virus and diseases related to HHV8 infection in Senegal.

Immunogenicity and protective efficacy of recombinant human T-cell leukemia/lymphoma virus type 1 NYVAC and naked DNA vaccine candidates in squirrel monkeys (Saimiri sciureus).

We assessed the immunogenicities and efficacies of two highly attenuated vaccinia virus-derived NYVAC vaccine candidates encoding the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) env gene or both the env and gag genes in prime-boost pilot regimens in combination with naked DNA expressing the HTLV-1 envelope. Three inoculations of NYVAC HTLV-1 env at 0, 1, and 3 months followed by a single inoculation of DNA env at 9 months protected against intravenous challenge with HTLV-1-infected cells in one of three immunized squirrel monkeys. Furthermore, humoral and cell-mediated immune responses against HTLV-1 Env could be detected in this protected animal. However, priming the animal with a single dose of env DNA, followed by immunization with the NYVAC HTLV-1 gag and env vaccine at 6, 7, and 8 months, protected all three animals against challenge with HTLV-1-infected cells. With this protocol, antibodies against HTLV-1 Env and cell-mediated responses against Env and Gag could also be detected in the protected animals. Although the relative superiority of a DNA prime-NYVAC boost regimen over addition of the Gag component as an immunogen cannot be assessed directly, our findings nevertheless show that an HTLV-1 vaccine approach is feasible and deserves further study.

Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.

BACKGROUND: Transmission of human herpesvirus 8 (HHV-8), the aetiological agent of Kaposi's sarcoma, is known to occur during sex among homosexual men. However, other modes of HHV-8 transmission remain to be elucidated in endemic populations. METHODS: We did a population-based seroepidemiological survey in a village in French Guiana among 1337 individuals of African origin (age 2-91 years) who had reliable genealogical data. Plasma samples were taken and tested for HHV-specific IgG by immunofluorescence assay. Risk factors and familial correlations for HHV-8 seropositivity were modelled by logistic regression analysis by use of the estimating equations approach, which expresses familial dependences in terms of odds ratios. Familial odds ratios were also acquired by use of the distribution of all possible pairs of a given familial dependence. FINDINGS: The overall HHV-8 seroprevalence was 13.2% with no difference according to sex. HHV-8 seropositivity was strongly age dependent: at 1.2% under 5 years, HHV-8 seroprevalence rose up to a plateau around 15% between 15 and 40 years, and showed a seroprevalence of more than 27% in individuals older than 40 years. Strong familial aggregation in HHV-8 seroprevalence was found with high mother-child (odd ratio 2.8 [95% CI 1.6-5.0]) and sib-sib (3.8 [1.6-9.5]) correlations. By contrast, no significant correlation between spouses (0.6 [0.2-1.9]) was seen. INTERPRETATION: This pattern of familial aggregation, together with the variation of HHV-8 seroprevalence with age, indicate that, in endemic populations, HHV-8 transmission mainly occurs from mother to child and between siblings during childhood and adolescence.

Detection of a major gene predisposing to human T lymphotropic virus type I infection in children among an endemic population of African origin.

Human T lymphotropic virus type I (HTLV-I) is a human oncoretrovirus that causes an adult T cell leukemia/lymphoma and a chronic neuromyelopathy. To investigate whether familial aggregation of HTLV-I infection (as determined by specific seropositive status) could be explained in part by genetic factors, we conducted a large genetic epidemiological survey in an HTLV-I-endemic population of African origin from French Guiana. All of the families in 2 villages were included, representing 83 pedigrees with 1638 subjects, of whom 165 (10.1%) were HTLV-I seropositive. The results of segregation analysis are consistent with the presence of a dominant major gene predisposing to HTLV-I infection, in addition to the expected familial correlations (mother-offspring, spouse-spouse) due to the virus transmission routes. Under this genetic model, approximately 1. 5% of the population is predicted to be highly predisposed to HTLV-I infection, and almost all seropositive children <10 years of age are genetic cases, whereas most HTLV-I seropositive adults are sporadic cases.

Lymphoid organs as a major reservoir for human T-cell leukemia virus type 1 in experimentally infected squirrel monkeys (Saimiri sciureus): provirus expression, persistence, and humoral and cellular immune responses.

The aim of this study was to investigate the distribution of human T-cell leukemia virus type 1 (HTLV-1) in various organs of serially sacrificed squirrel monkeys (Saimiri sciureus) in order to localize the reservoir of the virus and to evaluate the relationship between viral expression and the humoral or cellular immune response during infection. Six squirrel monkeys infected with HTLV-1 were sacrificed 6, 12, and 35 days and 3, 6, and 26 months after inoculation, and 20 organs and tissues were collected from each animal. PCR and reverse transcription-PCR (RT-PCR) were performed with gag and tax primers. Proviral DNA was detected by PCR in peripheral blood mononuclear cells (PBMCs) of monkeys sacrificed 6 days after inoculation and in PBMCs, spleens, and lymph nodes of monkeys sacrificed 12 and 35 days and 3, 6, and 26 months after inoculation. Furthermore, tax/rex mRNA was detected by RT-PCR in the PBMCs of two monkeys 8 to 12 days after inoculation and in the spleens and lymph nodes of the monkey sacrificed on day 12. In this animal, scattered HTLV-1 tax/rex mRNA-positive lymphocytes were detected by in situ hybridization in frozen sections of the spleen, around the germinal centers and close to the arterial capillaries. Anti-HTLV-1 cell-mediated immunity was evaluated at various times after inoculation. Anti-p40(Tax) and anti-Env cytolytic T-cell responses were detected 2 months after infection and remained detectable thereafter. When Tax peptides were used, this response appeared to be directed against various Tax epitopes. Our results indicate that squirrel monkeys represent a promising animal model for studying the early events of HTLV-1 infection and for evaluating candidate vaccines against HTLV-1.

Detection and genetic polymorphism of human herpes virus type 8 in endemic or epidemic Kaposi's sarcoma from West and Central Africa, and South America.

Kaposi's-sarcoma-associated herpesvirus(KSHV)/human-herpes-virus-8(HHV-8) sequences originally detected in AIDS-associated Kaposi's sarcoma have been found in almost every KS tested, whether endemic, classic, iatrogenic or epidemic. Most of the studies on African KS involved East African patients. We report herewith the study of 17 African or Guyanan KS patients, 3 with epidemic KS (EKS) from Central African Republic, 3 from Senegal (2 EKS and 1 endemic KS), 3 EKS from Cameroon and 8 from French Guiana (3 EKS and 5 endemic KS). Serum-specific antibodies directed against latent and/or lytic HHV-8 antigens were present in 16 of them (94%), detected either by immunofluorescence assay and/or by immunoperoxidase. Polymerase chain reaction (PCR), using specific primers for HHV-8 ORF26 (233 bp) and ORF75 (601 bp), was carried out on DNA extracted from KS cutaneous biopsies, clinically uninvolved skin biopsies and peripheral-blood mononuclear cells (PBMC). HHV-8 DNA was detected in 16 out of 16 (100%) KS biopsies, regardless of their origin or clinico-pathological sub-type, in 7 out of 15 (47%) normal skin samples and 7 out of 16 (44%) PBMC. Comparative PCR, carried out in 7 patients, regularly found a much higher viral load in KS biopsies than in autologous normal skin and PBMC samples. Sequencing of fragments of the ORF26 and of the ORF75 demonstrated that the 16 HHV-8 strains were of the A, B or C sub-type. Furthermore, sequences of the entire ORF K1 of 4 strains showed that these HHV-8 strains of African origin were of the A5 or the B sub-type.

Mother-to-child transmission of human T-cell-leukemia/lymphoma virus type I: implication of high antiviral antibody titer and high proviral load in carrier mothers.

In order to gain new insights into the risk factors influencing human-T-cell-leukemia/lymphoma-virus-type-I (HTLV-I) mother-to-child transmission, a retrospective study of HTLV-I infection among children born to HTLV-I-seropositive women was carried out in a highly HTLV-I-endemic population of African origin living in French Guyana. The study covered 81 HTLV-I-seropositive mothers and their 216 children aged between 18 months old and 12 years old. All plasma samples were tested for the presence of HTLV-I antibodies by ELISA, immunofluorescence assay and Western blot. HTLV-I provirus was detected, in the DNA extracted from peripheral-blood mononuclear cells, by polymerase chain reaction (PCR) using primers specific for 3 different HTLV-I genomic regions (LTR, gag and pX) and quantified by a competitive PCR assay. Out of the 216 children, 21 were found to be HTLV-I-seropositive, giving a crude HTLV-I transmission rate of 9.7%, while among the 180 breast-fed children 10.6% were HTLV-I-seropositive. Perfect concordance between serological and PCR results was observed, and none of the 195 HTLV-I-negative children was found HTLV-I-positive by PCR. In conditional (by family) logistic-regression models, HTLV-I seropositivity in children was associated with an elevated maternal anti-HTLV-I-antibody titer (OR 2.2, p = 0.0013), a high maternal HTLV-I proviral load (OR 2.6, p = 0.033) and child's gender, girls being more frequently HTLV-I-infected than boys: OR 3.6, p = 0.0077 in the model including maternal anti-HTLV-I-antibody titer and OR 4.1, p = 0.002 in the model including the maternal HTLV-I proviral load.

Seroepidemiological and molecular studies of human T cell lymphotropic virus type II, subtype b, in isolated groups of Mataco and Toba Indians of northern Argentina.

We studied plasma samples from 2082 Mataco Indians living in 22 different communities in the western part of Formosa Province, northern Argentina. Samples were screened for HTLV-I/II antibodies by particle agglutination assay. All positive or borderline samples were then tested by an immunofluorescence assay (IFA) on C19 HTLV-II-producing cells. Western blot was used for confirmation of all IFA-positive plasma samples. The crude HTLV-II seroprevalence was 3.0% (62 of 2051), and 0.9% (5 of 588) in children less than 10 years old. The latter result suggests ongoing mother-to-child transmission, probably by breast feeding. There was a marked increase in HTLV-II seroprevalence with age (0.9%, 0-10 years; 1.6%, 11-20 years; 4.4%, 21-30 years; 3.4%, 31-40 years; 7.2%, 41-50 years; 5.7%, >50 years) in both male (p = 0.002) and female subjects (p = 0.00002). None of the 80 non-Indian inhabitants tested was HTLV-I/II seropositive. In a second study, among 105 Toba Indians from a village (Primavera) of the eastern part of this region, 23 were HTLV-II seropositive with a seroprevalence of 59% in those more than 40 years old. From seven of the Indians from Primavera, three others from neighboring regions (including two Tobas and one Pilaga), and one intravenous drug user (IVDU) from Rosario, DNA was extracted from peripheral blood mononuclear cells, and the gp21 transmembrane-encoding gene (590 bp) was amplified by PCR, cloned, and sequenced. LTR sequences were also obtained from the Pilaga, the IVDU, and one Toba. Molecular and phylogenetic analyses revealed that the Indians were all infected with closely related HTLV-II molecular strains belonging to the b subtype, while the IVDU was infected with an HTLV-II subtype a variant. Such data help to make a phylogenetic atlas of HTLV-II among Amerindian tribes and are crucial to gain new insights into the origin and modes of dissemination of this human retrovirus in the Americas.

Human herpesvirus 8 primary infection occurs during childhood in Cameroon, Central Africa.

While in the United States and northern Europe, human herpesvirus 8 (HHV-8) appears to be mainly sexually transmitted with primary infection occurring in adulthood, the modes of transmission remain unknown in East and Central Africa, where Kaposi's sarcoma (KS) is a long-standing endemic disease, occurring not only in adults but also in children. The aim of our present study was to determine the prevalence of HHV-8 infection in children from Yaounde, Cameroon, Central Africa. Specific antibodies directed against both latent and lytic HHV-8 antigens were detected and titrated, with an immunofluorescence assay using the KS-1 cell line, in the plasma of 258 children and adolescents, of 32 mother and child pairs and of 189 pregnant women. Two different HHV-8 DNA-specific sequences were searched in the buffy coat by PCR assays. The overall HHV-8 seroprevalence was 27.5% among these children and adolescents. In newborns, seroprevalence reached 46%, reflecting passive transmission of maternal IgG. This was followed by a marked drop. Then, beginning around 4 years of age, a regular increase of HHV-8 antibodies took place, reaching 39% in the 12- to 14-year age group and 48% above 15 years, a rate similar (54.5%) to that observed in pregnant women. PCR detection of HHV-8 sequences was negative in seronegative children and positive in the buffy coat in 17% of HHV-8-seropositive children, reflecting a low viral load in the peripheral blood. Our results establish that in Central Africa HHV-8 infection takes place during childhood by casual routes, in contrast to the sexual transmission observed in adults in northern Europe and the United States. We hypothesize that the lymphadenopathic form of KS seen in African children is related to an early and massive infection by HHV-8 in susceptible individuals.

Demographic and familial characteristics of HTLV-1 infection among an isolated, highly endemic population of African origin in French Guiana.

To determine the epidemiological characteristics of human T cell leukemia/lymphoma virus type I (HTLV-I) infection in the endemic village of Maripasoula, French Guiana, 1,614 persons (83.2% of the population) aged 2 to 91 years (mean age 21) were studied from November 1994 through April 1995. Plasma samples were screened by an HTLV-I ELISA and an IFA test (on MT2 cells), and positive samples were tested by an HTLV-I and -II type-specific Western blot. Overall seropositivity in the village was 6.7%, but HTLV-I infection was restricted to 3 of 6 ethnic groups, including the Noir-Marron (descendants of escaped African slaves, 8%), the Creoles (4.1%) and those of mixed Noir Marron/other ethnicity (3.6%). In the Noir-Marron population of 1,222 persons, including 606 men and 616 women and representing 76% of those tested, HTLV-I seroprevalence increased significantly with age in both sexes, reaching 40% in women older than 50 years. Univariate risk factors for HTLV-I seropositivity in women included older age, more pregnancies, more live births and a history of hospitalization. A cross-sectional analysis of sexual partners demonstrated an excess of discordant female HTLV-I+/male HTLV-I- couples, indicating preferential male-to-female sexual transmission. The demonstration of II HTLV-I-seropositive children aged less than 15 years, of whom 9 had a seropositive mother, suggested maternal-child HTLV-I transmission. Our results demonstrate a very high seroprevalence of HTLV-I in this South American population descended from African slaves, probably due to high rates of mother-to-child and sexual transmission within this rather isolated group.

Cutaneous T cell lymphomas: mycosis fungoides, Sezary syndrome and HTLV-I-associated adult T cell leukemia (ATL) in Mali, West Africa: a clinical, pathological and immunovirological study of 14 cases and a review of the African ATL cases.

Cutaneous T cell lymphomas (CTCL) are rare lymphoproliferative diseases, which are frequently suspected to be of viral origin. As very few data were available concerning cutaneous T cell lymphomas in tropical Africa, we undertook a clinical, histopathological, immunological and viro-molecular study of patients with a clinical diagnosis of cutaneous lymphoma, in Bamako, Mali. While prior to this study, no case of CTCL had been reported in this country, 14 patients (five women, nine men; mean age 58 years) with a diagnosis of cutaneous lymphoma were seen over a period of 30 months (1992-1994) in the only dermatological department in Mali. Clinically, the most frequent pattern was an infiltrated erythrodermia similar to Sezary syndrome. Nodular lesions and/or plaques were rarely observed. All these cutaneous tumors were T cell lymphoproliferations, only one expressing the CD8+ antigen. A comprehensive analysis of all the available data permitted characterization of three cases of adult T cell leukemia/lymphoma (ATL) associated with HTLV-I (one definitive case, of leukemic type, with demonstration of clonal integration of HTLV-I proviral genome and two probable ATL cases), three cases of Sezary syndrome (SS), two cases of mycosis fungoides (MF) and five cases of pleomorphic cutaneous lymphoma. In one case, the differentiation between MF and pleomorphic cutaneous lymphoma could not be established. HTLV-I serological and/or molecular markers were restricted to the three ATL cases. From the unique definitive ATL case, a T cell line was established from culture of peripheral blood mononuclear cells and sequence analysis of the env gene and the U3-LTR region demonstrated that the virus present in this patient belonged to the cosmopolitan subtype A. Thus, we report here the first evidence of HTLV-I infection and associated ATL in Mali. This is the second ATL case described for the whole Sahelian region (one ATL of the lymphoma type was reported previously in a Mauritanian patient). Furthermore, we demonstrate that the main types of CTCL described in Europe and North America are also present in this African area and that the prevalence of these diseases is greatly underestimated in such regions. Furthermore, no association was observed between HTLV-I/II infection and SS, MF or pleomorphic cutaneous lymphoma in Mali in contrast to other studies.

Molecular epidemiology of HTLV-II among United States blood donors and intravenous drug users: an age-cohort effect for HTLV-II RFLP type aO.

Molecular subtyping was used to investigate the epidemiology of human T-lymphotropic virus type II (HTLV-II) in the United States. Nested polymerase chain reaction of the HTLV-II long terminal repeat region followed by restriction fragment length polymorphism (RFLP) analysis was performed on HTLV-II seropositive subjects including 97 U.S. blood donors without major risk factors for HTLV-II infection, 53 injection drug users (IDU), and 10 American Indian blood donors. Three new HTLV-II RFLP types were confirmed with DNA sequencing and phylogenetic analysis. HTLV-II RFLP type aO (Switzer classification) was associated with older age [adjusted odds ratio (OR) 1.06 per year of age, 95% confidence interval (CI) 1.02-1.09] and with Black (OR 5.24, 95% CI 1.90-14.47) and White (OR 4.43, 95% CI 1.67-11.75) race/ethnicity. These data are consistent with an age-cohort effect for HTLV-II RFLP type aO among older White and Black IDU and blood donors. This finding could be explained by an epidemic of non-aO HTLV-II RFLP types among younger persons of Hispanic and other race/ethnicity, superimposed upon endemic HTLV-II RFLP type aO among older Black and White persons.