Antoine Gessain

ANTIBODIES TO HUMAN T-LYMPHOTROPIC VIRUS TYPE-I IN PATIENTS WITH TROPICAL SPASTIC PARAPARESIS

10 out of 17 (59%) patients with tropical spastic paraparesis (TSP) had antibodies to human T-lymphotropic virus-I (HTLV-I), as did 5 out of 5 TSP patients with systemic symptoms. Only 13 out of 303 (4%) controls, made up of blood donors, medical personnel, and other neurological patients, had such antibodies. These findings suggest either that HTLV-I is neurotropic or that the virus or a related one contributes to the pathogenesis of TSP.

Epidemiological Aspects and World Distribution of HTLV-1 Infection

The human T-cell leukemia virus type 1 (HTLV-1), identified as the first human oncogenic retrovirus 30 years ago, is not an ubiquitous virus. HTLV-1 is present throughout the world, with clusters of high endemicity located often nearby areas where the virus is nearly absent. The main HTLV-1 highly endemic regions are the Southwestern part of Japan, sub-Saharan Africa and South America, the Caribbean area, and foci in Middle East and Australo-Melanesia. The origin of this puzzling geographical or rather ethnic repartition is probably linked to a founder effect in some groups with the persistence of a high viral transmission rate. Despite different socio-economic and cultural environments, the HTLV-1 prevalence increases gradually with age, especially among women in all highly endemic areas. The three modes of HTLV-1 transmission are mother to child, sexual transmission, and transmission with contaminated blood products. Twenty years ago, de Thé and Bomford estimated the total number of HTLV-1 carriers to be 10–20 millions people. At that time, large regions had not been investigated, few population-based studies were available and the assays used for HTLV-1 serology were not enough specific. Despite the fact that there is still a lot of data lacking in large areas of the world and that most of the HTLV-1 studies concern only blood donors, pregnant women, or different selected patients or high-risk groups, we shall try based on the most recent data, to revisit the world distribution and the estimates of the number of HTLV-1 infected persons. Our best estimates range from 5–10 millions HTLV-1 infected individuals. However, these results were based on only approximately 1.5 billion of individuals originating from known HTLV-1 endemic areas with reliable available epidemiological data. Correct estimates in other highly populated regions, such as China, India, the Maghreb, and East Africa, is currently not possible, thus, the current number of HTLV-1 carriers is very probably much higher.

Characterization of Reemerging Chikungunya Virus

An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host.

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 Kaposis 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.

Meta-Analysis on the Use of Zidovudine and Interferon-Alfa in Adult T-Cell Leukemia/Lymphoma Showing Improved Survival in the Leukemic Subtypes

PURPOSE Human T-cell lymphotropic virus type-I-associated adult T-cell leukemia/lymphoma (ATL) is an aggressive, chemotherapy-resistant malignancy. Multiple small studies using zidovudine (AZT) and interferon-alfa (IFN-α) have shown response in patients with ATL. However, the impact of this innovative antiviral treatment strategy on long-term survival remains undetermined. PATIENTS AND METHODS We report a meta-analysis of antiviral therapy of ATL. Medical records of 254 patients with ATL who were treated in the United States, the United Kingdom, Martinique, and continental France were individually reviewed. RESULTS According to Shimoyama classification, there were 116 patients with acute ATL, 18 patients with chronic ATL, 11 patients with smoldering ATL, and 100 patients with ATL lymphoma. In 231 patients with available survival data, first-line therapy was recorded in 207 patients. Five-year overall survival rates were 46% for 75 patients who received first-line antiviral therapy (P = .004), 20% for 77 patients who received first-line chemotherapy, and 12% for 55 patients who received first-line chemotherapy followed by antiviral therapy. Patients with acute, chronic, and smoldering ATL significantly benefited from first-line antiviral therapy, whereas patients with ATL lymphoma experienced a better outcome with chemotherapy. In acute ATL, achievement of complete remission with antiviral therapy resulted in 82% 5-year survival. Antiviral therapy in chronic and smoldering ATL resulted in 100% 5-year survival. Multivariate analysis confirmed that first-line antiviral therapy significantly improves overall survival of patients with ATL (hazard ratio, 0.47; 95% CI, 0.27 to 0.83; P = .021). CONCLUSION These results confirm the high efficacy of AZT and IFN, which should now be considered the gold standard first-line therapy in leukemic subtypes of ATL.

Human Muscle Satellite Cells as Targets of Chikungunya Virus Infection

Background Chikungunya (CHIK) virus is a mosquito-transmitted alphavirus that causes in humans an acute infection characterised by fever, polyarthralgia, head-ache, and myalgia. Since 2005, the emergence of CHIK virus was associated with an unprecedented magnitude outbreak of CHIK disease in the Indian Ocean. Clinically, this outbreak was characterized by invalidating poly-arthralgia, with myalgia being reported in 97.7% of cases. Since the cellular targets of CHIK virus in humans are unknown, we studied the pathogenic events and targets of CHIK infection in skeletal muscle. Methodology/Principal Findings Immunohistology on muscle biopsies from two CHIK virus-infected patients with myositic syndrome showed that viral antigens were found exclusively inside skeletal muscle progenitor cells (designed as satelllite cells), and not in muscle fibers. To evaluate the ability of CHIK virus to replicate in human satellite cells, we assessed virus infection on primary human muscle cells; viral growth was observed in CHIK virus-infected satellite cells with a cytopathic effect, whereas myotubes were essentially refractory to infection. Conclusions/Significance This report provides new insights into CHIK virus pathogenesis, since it is the first to identify a cellular target of CHIK virus in humans and to report a selective infection of muscle satellite cells by a viral agent in humans.

Chronic Myelopathy Associated with Human T-Lymphotropic Virus Type I (HTLV-I)

PURPOSE To review the clinical, epidemiologic, immunologic, and virologic aspects of the chronic myelopathy associated with human T-cell leukemia/lymphoma virus type I (HTLV-I), currently called tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). DATA IDENTIFICATION Studies done after 1985, when TSP/HAM was first recognized, were identified by a computer search using MEDLARS II and CANCERLIT. Additional information was acquired from personal files and bibliographies of existing literature. STUDY SELECTION A total of 400 articles, 90 book chapters, and 150 abstracts from meetings covering all aspects of HTLV-I and neurologic diseases were critically analyzed, and information from 250 publications was included. RESULTS OF DATA ANALYSIS TSP/HAM is present in most HTLV-I endemic areas, with a prevalence ranging from 5.1 to 128 per 100,000 inhabitants. Up to 20% of patients develop TSP/HAM after transfusion of HTLV-I contaminated blood. Pathologic characteristics indicate a chronic meningomyelitis. The clinical features consist of a chronic progressive spastic paraparesis or paraplegia, sphincter disturbances, and minimal sensory loss. Supraspinal and peripheral nerve involvement is sometimes observed. High titers of HTLV-I-specific antibodies are present in the serum and cerebrospinal fluid. The high level of humoral and cellular immunologic response and the association of TSP/HAM with other immunologic diseases suggest an immune-mediated process. Corticosteroids and immunosuppressor treatment usually result in only short-term improvement. CONCLUSION TSP/HAM is a common neurologic disease in many parts of the world. All patients with chronic progressive myelopathies should be tested for serum and cerebrospinal fluid HTLV-I-specific antibodies. Systematic screening of blood donors for HTLV-I is necessary to help prevent the dissemination of the virus and the occurrence of post-transfusional cases.

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 Kaposis 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 Yaoundé, 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. Int. J. Cancer 81:189–192, 1999.

Maternal traces of deep common ancestry and asymmetric gene flow between Pygmy hunter–gatherers and Bantu-speaking farmers

Two groups of populations with completely different lifestyles—the Pygmy hunter–gatherers and the Bantu-speaking farmers—coexist in Central Africa. We investigated the origins of these two groups and the interactions between them, by analyzing mtDNA variation in 1,404 individuals from 20 farming populations and 9 Pygmy populations from Central Africa, with the aim of shedding light on one of the most fascinating cultural transitions in human evolution (the transition from hunting and gathering to agriculture). Our data indicate that this region was colonized gradually, with an initial L1c-rich ancestral population ultimately giving rise to current-day farmers, who display various L1c clades, and to Pygmies, in whom L1c1a is the only surviving clade. Detailed phylogenetic analysis of complete mtDNA sequences for L1c1a showed this clade to be autochthonous to Central Africa, with its most recent branches shared between farmers and Pygmies. Coalescence analyses revealed that these two groups arose through a complex evolutionary process characterized by (i) initial divergence of the ancestors of contemporary Pygmies from an ancestral Central African population no more than ≈70,000 years ago, (ii) a period of isolation between the two groups, accounting for their phenotypic differences, (iii) long-standing asymmetric maternal gene flow from Pygmies to the ancestors of the farming populations, beginning no more than ≈40,000 years ago and persisting until a few thousand years ago, and (iv) enrichment of the maternal gene pool of the ancestors of the farming populations by the arrival and/or subsequent demographic expansion of L0a, L2, and L3 carriers.

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 childs 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. Int. J. Cancer 82:832–836, 1999.