HTLV-1 and tropical spastic paraparesis. 2. The human T-cell lymphotropic virus type 1

Human T-lymphotropic viruses (HTLV) are causally associated with adult T-cell leukaemia and with a progressive form of lower limb paralysis known as tropical spastic paraparesis. HTLV-1 is endemic in parts of Japan, the Caribbean, West Africa and probably South America, and is associated with disease in these areas. Horizontal transmission is probably most common through sexual intercourse which, it is postulated, must be more efficient from male to female because virus carriage is more prevalent in women in endemic areas. Vertical transmission appears to be principally through breast milk. Poor housing and hygiene may facilitate transmission.     

Probable HTLV-I/II Tropical Spastic Paraparesis Patient from Ethiopia: A Case Report

BackgroundAvailable data on the burden of Human T-cell lymphotropic virus type I/II infection for eastern Africa, limited to Ethiopia, Mozambique, and Rwanda, show prevalence lower than elsewhere in Africa (0% – 1.8%). Even if Tropical Spastic Paraparesis occurs in an endemic form in Ethiopia, its seroprevalence is low. Over a lifetime, it is estimated that 1–2% of Human T-cell lymphotropic virus type I/ II -infected individuals will develop progressive and disabling inflammatory clinical manifestations. We are reporting this case since it signifies the existence of seropositive Tropical Spastic Paraparesis in our setting and the need to properly diagnose this condition.Case PresentationWe are reporting a 45 years old female patient from Addis Ababa, Ethiopia, who presented with progressive weakness of the lower limbs and urinary urge incontinence of five years duration. Serology for Human T-cell lymphotropic virus type I/ II antibody was positive. She was diagnosed to have probable tropical spastic paraparesis after fulfilling World Health Organization diagnostic criteria for tropical spastic paraparesis with the level of ascertainment. Symptoms showed transient improvements after providing five days of Methylprednisolone followed by low doses of corticosteroids and Azathioprine. The patient is now significantly disabled and wheelchair-bound.ConclusionsThe patient described here signifies a probable Human T-cell lymphotropic virus type I/ II - associated myelopathy/tropical spastic paraparesis in Ethiopian women. This case highlights the existence of Human T-cell lymphotropic virus type I/II - associated myelopathy/ tropical spastic paraparesis within our setting and the need to properly diagnose this condition.     

Analyses of HTLV-1 sequences suggest interaction between ORF-I mutations and HAM/TSP outcome

The region known as pX in the 3′ end of the human T-cell lymphotropic virus type 1 (HTLV-1) genome contains four overlapping open reading frames (ORF) that encode regulatory proteins. HTLV-1 ORF-I produces the protein p12 and its cleavage product p8. The functions of these proteins have been linked to immune evasion and viral infectivity and persistence. It is known that the HTLV-1 infection does not necessarily imply the development of pathological processes and here we evaluated whether natural mutations in HTLV-1 ORF-I can influence the proviral load and clinical manifestation of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). For that, we performed molecular characterization, datamining and phylogenetic analysis with HTLV-1 ORF-I sequences from 156 patients with negative or positive diagnosis for HAM/TSP. Our analyses demonstrated that some mutations may be associated with the outcome of HAM/TSP (C39R, L40F, P45L, S69G and R88K) or with proviral load (P34L and F61L). We further examined the presence of mutations in motifs of HBZ and observed that P45L mutation is located within the HBZ nuclear localization signal and was found more frequently between patients with HAM/TSP and high proviral load. These results indicate that some natural mutations are located in functional domains of ORF-I and suggests a potential association between these mutations and the proviral loads and development of HAM/TSP. Therefore it is necessary to conduct functional studies aimed at evaluating the impact of these mutations on the virus persistence and immune evasion.     

Delimitation of the upstream region of NFKBIA gene associated with HTLV-1-associated myelopathy/tropical spastic paraparesis using candidate Tag-SNPs in Peruvian HTLV-1 infected individuals

In Peru, it is estimated that about 150 000-400 000 people carry the Human T-lymphotropic virus 1 (HTLV-1). Only 10% of HTLV-1 carries develop complications related to HTLV-1. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic disabling inflammatory disease affecting the spinal cord. HAM/TSP produces principally weakness in the lower limbs and bladder disturbances, among other complications. In a previous study, our group identified three SNPs (rs3138053, rs2233406, and rs3138045) located in the promoter region of the NFKBIA gene associated with HAM/TSP. This study aimed to analyze the association between four Tag-SNPs (rs10148482, rs17103274, rs17103282, and rs762009) located in the upstream region of the NFKBIA gene and HAM/TSP, and to delimit the linkage disequilibrium zone in the upstream region of the NFBKIA gene associated with HAM/TSP. The tetra-primers ARMS-PCR technique was used to genotype 4 Tag-SNPs on 140 HAM/TSP patients and 258 asymptomatic carriers. The SNP rs17103282 showed a deviation from Hardy-Weinberg equilibrium (p < .0001). Neither of three Tag-SNPs showed an association with HAM/TSP (P > .05). No linkage disequilibrium between four Tag-SNPs evaluated in this study and previous ones was observed. Here we show the region located in the upstream region of the NFKBIA gene highly associated with HAM/TSP disease in patients infected with HTLV-1 from Lima, Peru.     

Low HTLV-1 seroprevalence in endemic tropical spastic paraparesis in Ethiopia

Tropical spastic paraparesis (TSP), a chronic progressive myelopathy, occurs in Ethiopia in epidemic form as neurolathyrism, while the endemic form has remained obscure. We describe the clinical features of 22 patients with TSP and the results of screening for HTLV-1 in these patients, 26 patients with other neurological disorders, 14 patients with leukaemia and 66 blood donors. The major manifestations in the patients with TSP were weakness and spasticity of the lower limbs with upper motor neurone signs and minimal sensory loss and bladder dysfunction. Two patients with TSP (9%), 2 patients with other neurological disorders (7.7%) and one patient with leukaemia and deafness were seropositive for HTLV-1. All the 66 blood donors were seronegative. Our results suggest that HTLV-1 may not play a major role in the pathogenesis of TSP in Ethiopia.     

HTLV seroepidemiology in a central African population with high incidence of tropical spastic paraparesis

In Lisala (Equateur region, Zaire), where a cluster of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) was described, 28/200 (14%) out-patients and hospital personnel were HTLV antibody positive. No differences in prevalences were observed between out-patients and hospital personnel or between ethnic groups. The annual attack rate of TSP/HAM is estimated at 0.15-0.3 per 1000 infected. The ethnic and familial clustering of TSP/HAM together with the high attack rate suggests the presence of co-factors for the progression to disease. This high prevalence of HTLV antibodies contrasts with the low prevalence in another part of the Equateur region.     

Phylogenetic and phylodynamic study of Human T-cell lymphotropic virus Type 1 (HTLV-1) in Iran

Human T-lymphotropic virus type-1 (HTLV-1) is a retrovirus that causes the neurological disorder HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) and/or adult T-cell leukemia/lymphoma (ATLL). Iran is one of the endemic regions of the HTLV-1 in the Middle East. To infer the origin of the virus in Iran and to follow the movements of human population and routes of virus spread to this country, phylogenetic and phylodynamic analyses were performed. To this purpose, the long terminal repeat (LTR) region of HTLV-1 was used. New LTR sequences were obtained from 100 blood samples which infected with HTLV-1. Moreover, all Iranian LTR sequences which have been reported so far, were obtained from GenBank database. Sequences were aligned and maximum-likelihood and Bayesian tree topologies were explored. After identification of Iranian specific cluster, molecular-clock and coalescent models were used to estimate time to the most recent common ancestor (tMRCA). Bayesian Skyline Plots (BSP), representing population dynamics HTLV-1 strains back to the MRCA, were estimated using BEAST software. Phylogenetic analysis demonstrated that the Iranian, Kuwaiti, German, Israelite and southern Indian isolates are located within the widespread “transcontinental” subgroup A clade of HTLV-1 Cosmopolitan subtype a. Molecular clock analysis of the Iranian cluster dated back their respective tMRCA to be 1290 AC with a 95% HPD confidence intervals (918, 1517). BSPs indicated a rapid exponential growth rate in the effective number of infections prior the 15th century. Our results support the hypothesis of a multiple introductions of HTLV-1 into Iran with the majority of introductions occurring in prior the 15th century, at the same time the Mongol invasion of Iran. Our results further suggest that HTLV-1 introduction into Iran was facilitated by the commercial/migratory linkage as known as the ancient Silk Road which linked China to Antioch (now in Turkey).     

Impact of depression on quality of life in people living with human T cell lymphotropic virus type 1 (HTLV-1) in Salvador, Brazil

Purpose

A previous study found the prevalence of depression in HTLV-1-infected patients to be approximately 30%, but few studies have attempted to correlate depression with quality of life (QOL) in these patients. The present study investigates the association between depression and QOL in people living with HTLV-1.

Methods

A clinical-epidemiological questionnaire, the Mini International Neuropsychiatric Interview and the WHOQOL-Bref were applied to 88 HTLV-1-infected patients (32 with TSP/HAM) at the HTLV Center of the Bahiana School of Medicine and Public Health, Salvador, Brazil.

Results

The prevalence of depression among people living with HTLV-1 was 34.1%. Depression was significantly associated with a poor QOL in the physical, psychological, social relationship and environment domains, when controlling for other variables, such as gender, age, time of knowledge of serological diagnosis and presence of tropical spastic paraparesis/HTLV-1associated myelopathy (TSP/HAM). Moreover, patients with TSP/HAM experienced a reduction in their QOL in the physical, psychological and environment domains.

Conclusion

Our results showed that depression negatively affects the quality of life of people living with HTLV-1, regardless of the presence of TSP/HAM. Since it is possible to improve a patient??s QOL by treating depression, psychological evaluations are strongly recommended as a measure to integrate the treatment protocols of HTLV-1 intervention programs.     

Mantakassa: an epidemic of spastic paraparesis associated with chronic cyanide intoxication in a cassava staple area of Mozambique. 1. Epidemiology and clinical and laboratory findings in patients

Investigation of an epidemic of more than 1000 cases of spastic paraparesis in a drought-striken cassava staple area of Mozambique strongly suggests an association between this disease (called mantakassa), chronic cyanide intoxication, and cassava consumption. In previous reports of neurological disease with similar associations, the disease affected an older age group with usually a gradual onset, and the predominant clinical feature was an ataxic neuropathy. In mantakassa the onset was acute, and mostly women of reproductive age and children were affected. Serum thiocyanate levels in these patients were much higher than previously reported; while spastic paraparesis of unknown etiology occurs in many tropical countries, it has not previously been linked with raised thiocyanate levels. The present evidence linking cassava consumption to the disease is circumstantial, and dietary deficiency is also probably involved. Cassava is an important food crop and a major source of energy for people in many parts of the world. In these areas, when there is a shortage of food production, e.g., during a drought, the inhabitants may be exposed to the risk of dietary cyanide intoxication. Further research is needed on the causes of mantakassa so that a repetition of this disaster could be prevented.     

HTLV-I-associated myelopathy (HAM/TSP) with Hashimoto's thyroiditis.

Two cases of HTLV-I-associated myelopathy (HAM/TSP) with Hashimoto's thyroiditis are reported. One patient is a 47-year-old female with goiter and the other a 60-year-old female. Both have slowly progressive spastic paraparesis and have anti-HTLV-I antibodies in their serum and cerebrospinal fluid. Anti-thyroid antibodies are also present in their serum, and biopsy specimens of their thyroids showed the pathological features of Hashimoto's thyroiditis. The association of the two disorders in these patients provides further evidence for the autoimmune hypothesis of the pathogenesis of HAM/TSP, and also suggests a relationship of Hashimoto's thyroiditis with HTLV-I infection.     

HTLV-1 infection in Reunion

Objectives

Although regularly looked for in blood donors, HTLV infections are very rare in Reunion. We aimed to describe HTLV infections locally.

In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection

Human T-cell leukemia virus type 1 (HTLV-1) has infected as many as 10 million people worldwide. While 90% are asymptomatic, 5% develop severe diseases including adult T-cell leukemia/lymphoka (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). No vaccine against HTLV-1 exists, and screening programs are not universal. However, patients with chronic HTLV-1 infection have high frequencies of HTLV-1-activated CD8+ T cells, and the two main HLA alleles (A2, A24) are present in 88% of infected individuals. We thus utilized an immunoproteomics approach to characterize MHC-I restricted epitopes presented by HLA-A2+, A24+ MT-2 and SLB-1 cell lines. Unlike traditional motif prediction algorithms, this approach identifies epitopes associated with cytotoxic T-cell responses in their naturally processed forms, minimizing differences in antigen processing and protein expression levels. Out of nine identified peptides, we confirmed six novel MHC-I restricted epitopes that were capable of binding HLA-A2 and HLA-A24 alleles and used in vitro and in vivo methods to generate CD8+ T cells specific for each of these peptides. MagPix MILLIPLEX data showed that in vitro generated epitope-specific CD8+ T cells secreted IFN-ɣ, granzyme B, MIP-1α, TNF-α, perforin and IL-10 when cultured in the presence of MT-2 cell line. Degranulation assay confirmed cytotoxic response through surface expression of CD107 on CD8+ T cells when cultured with MT-2 cells. A CD8+ T-cell killing assay indicated significant antiviral activity of CD8+ T cells specific against all identified peptides. In vivo generated CD8+ T cells similarly demonstrated immunogenicity on ELISpot, CD107 degranulation assay, and MagPix MILLIPLEX analysis. These epitopes are thus candidates for a therapeutic peptide-based vaccine against HTLV-1, and our results provide preclinical data for the advancement of such a vaccine.     

Human T-cell lymphotropic virus testing of blood donors in Norway: a cost-effect model

BACKGROUND: Human T-cell lymphotropic virus type I and II (HTLV-I and II) are human retroviruses that can be transmitted by transfusion of whole blood. An HTLV-I infection is associated with adult T-cell leukaemia (ATL) and with tropical spastic paraparesis (TSP). Antibody tests from 5.5 million European blood donors have shown that the HTLV prevalence is low, ranging from 0 to 0.02%. This paper examines costs and effects associated with the intervention of testing all new blood donors for HTLV. METHODS: A mathematical model was used to calculate the number of cases prevented by the intervention. For a given prevalence of HTLV in the blood donor population, the model calculates the number of recipients infected by transfusion, and the number of partners and offspring that will in turn be infected. The model then calculates the number of subjects with disease due to HTLV-I infection and the number of deaths from disease. From these numbers the measures of cost and effect are calculated. RESULTS: Testing all new blood donors for HTLV is calculated to cost US$ 9.2 million per life saved, or US$ 420,000 per quality adjusted life year gained by the intervention, when the HTLV prevalence among donors is 1 per 100,000. When the prevalence among donors is 10 per 100,000 the intervention will cost US$ 0.9 million per life saved, or US$ 41,000 per quality adjusted life year gained. The same analysis shows that testing blood donors for human immunodeficiency virus (HIV) saves money when the HIV prevalence among donors is above 0.7 per 100,000. CONCLUSION: For Norway, studies suggest a willingness to pay to save a statistical life of approximately US$ 1.2 million. The costs fall under this value when the number of infected persons is > or = 8 per 100,000 donors. The results are uncertain because of the uncertainty in HTLV infection and disease parameters.     

Epidemiology and long-term consequences of hepatitis delta virus infection in the Yucpa Indians of Venezuela.

To define better the epidemiology and clinical impact of hepatitis delta virus (HDV) infection among hepatitis B virus (HBV) carriers in less developed countries, the authors prospectively studied a cohort of 216 Yucpa Indian HBV carriers in Venezuela. HBV carriers were followed regularly between 1983 and 1988 by physical examination, laboratory testing for liver enzymes and HBV and HDV markers, and epidemiologic history. Among the cohort, 74 (34%) were initially positive for HDV infection, and 35 additional persons became infected during the study. Risk factors for new HDV infection included living in southern Yucpa villages; being young adults (15-19 years) or young children (1-9 years), and living in a household with a person with acute HDV infection. Persons with HDV infection were at high risk of developing chronic liver disease; 56% of HDV-infected persons had moderate-to-severe chronic liver disease at the end of the study compared with none of the HBV carriers without HDV infection. Mortality rates were 6.9% and 8.8% per year, respectively, among initially HDV-positive HBV carriers and those with new HDV infection, because of rapidly progressive chronic liver disease and fulminant hepatitis; mortality was significantly lower in HBV carriers without HDV infection and in non-HBV carriers. HDV superinfection is a devastating disease in HBV carriers in tropical South America. Prevention of HBV infection with hepatitis B vaccine is the best available tool to reduce the impact of this problem.     

Phylodynamics of influenza A(H3N2) in South America, 1999–2012

The limited influenza A(H3N2) genetic data available from the Southern Hemisphere (particularly from Africa and Latin America), constrains the accurate reconstruction of viral dissemination dynamics within those regions. Our objective was to describe the spatial dissemination dynamics of influenza A(H3N2) within South America. A total of 469 sequences of the HA1 portion of the hemagglutinin gene (HA) from influenza A(H3N2) viruses sampled in temperate and tropical South American countries between 1999 and 2012 were combined with available contemporary sequences from Australia, Hong Kong, United Kingdom and the United States. Phylogenetic analyses revealed that influenza A(H3N2) sequences from South America were highly intermixed with sequences from other geographical regions, although a clear geographic virus population structure was detected globally. We identified 14 clades mostly (≥ 80%) composed of influenza sequences from South American countries. Bayesian phylogeographic analyses of those clades support a significant role of both temperate and tropical regions in the introduction and dissemination of new influenza A(H3N2) strains within South America and identify an intensive bidirectional viral exchange between different geographical areas. These findings indicate that seasonal influenza A(H3N2) epidemics in South America are seeded by both the continuous importation of viral variants from other geographic regions and the short-term persistence of local lineages. This study also supports a complex metapopulation model of influenza A(H3N2) dissemination in South America, with no preferential direction in viral movement between temperate and tropical regions.     

The risk of yellow fever in travellers

Yellow fever is a tropical virus disease characterised by high fever, jaundice, heart and kidney failure, and haemorrhagic diathesis. The causative Flavivirus is endemic in parts of tropical Africa and South America and is transmitted among humans and primates by mosquitoes. The chance that an unvaccinated traveller to West Africa will die of yellow fever is estimated at 1:650 to 1:5000 visitors per month of stay, depending on whether an epidemic occurs. Vaccination with the attenuated yellow fever Asibi 17D virus results in limited virus replication in the body and long-term protection due to the formation of neutralising antibodies. Vaccination is contraindicated in immunocompromised persons. Serious disseminated disease and encephalitis due to infection with the vaccine virus strain are seen more often in the elderly. One should therefore refrain from vaccination in persons over 60 years of age when the risk of infection is negligible. In recent years, the number of yellow fever epidemics has risen substantially, particularly in West Africa and the Amazon region. Reintroduction of yellow fever vaccination in childhood vaccination programmes is necessary in endemic areas to turn the tide of increasing outbreaks of yellow fever.     

Serosurvey for "acute hemorrhagic conjunctivitis" virus (Enterovirus 70) antibodies in the Southeastern United States, with review of the literature and some epidemiologic implications.

Acute hemorrhagic conjunctivitis (AHC) has been epidemic throughout much of the Eastern Hemisphere since its emergence in central West Africa in 1969. The disease had a distinctive clinical picture and an unusual geographic epidemiology. Between 1969 and 1975 AHC has occurred almost exclusively in crowded coastal areas of tropical countries during hot, rainy seasons. Only a few documented outbreaks have occurred in inland cities and in subtropical or temperate climate zones. Of 1014 residents of the eastern or southeastern United States who were screende for neutralizing antibodies to three or four strains of AHC virus (enterovirus type 70), three (0.3%) had titers ranging from 1:10 to 1:40. However, no clinical evidence of prior experience with AHC disease could be ascertained for these persons, so that the antigenic specificity of the detected antibodies is unknown. We conclude that populations of coastal tropical areas of northern South America and all of Central America are vulnerable to AHC epidemics.     

Fièvre jaune,dengue, encéphalite japonaise et virose West Nile, 4 arboviroses majeures

Yellow fever, Dengue, Japanese encephalitis, and West Nile virus infection are induced by 4 strongly epidemic major arboviruses. Despite its vaccine, yellow fever remains very active in tropical Africa and in South America. The insufficient immunization coverage and population mobility explain the permanence of the epidemics. Vaccination is essential for travelers going to endemic regions. The prevalence of dengue has increased considerably in the last decades. The number of countries concerned with its hemorrhagic forms is also increasing. It is the most frequently observed arbovirus disease in travelers. Widespread in Asia, Japanese encephalitis can be prevented by a specific vaccination. The development of tourism to endemic areas raises the issue of risks for travelers and what preventive measures may be available. The West Nile virus has been present in North America since 1999. There, it caused the most severe epidemic ever observed, in the summer 2002. The clinical expression of the disease has changed over the last 10 years. Initially regarded as a benign virus, it is now considered as being able to cause neurological forms with a high death rate, particularly in elderly people.     

Mantakassa: an epidemic of spastic paraparesis associated with chronic cyanide intoxication in a cassava staple area of Mozambique. 2. Nutritional factors and hydrocyanic acid content of cassava products

An outbreak of spastic paraparesis which mostly affected women and children occurred in a northern province of Mozambique in 1981. The epidemic was related to chronic cyanide intoxication associated with a diet consisting almost exclusively of cassava. A prolonged drought in the area had exhausted all food resources except cassava, especially the bitter varieties. A nutritional, toxicological and botanical investigation was carried out in two of the five districts affected. The main findings were that cyanide levels were unusually high in the cassava plant as a consequence of the drought with daily intakes estimated at 15-31.5 mg HCN. Detoxification of the bitter varieties by sun-drying was inadequate because of the general food shortage, and metabolic detoxification was probably reduced owing to the absence of sulfur-containing amino acids in the diet. The raw and dried uncooked cassava was eaten mostly by women and children. The nutritional status of the population, however, was not very poor and symptoms of advanced under-nutrition were rarely seen.