HTLV-1 Infection Research Articles

Estimation of HTLV-1 vertical transmission cases in Brazil per annum.

BackgroundBrazil has at least 800,000 HTLV-1 infected individuals. HTLV-1 can be transmitted via sexual intercourse, contact with blood and from mother to child, mainly by breastfeeding. Treatments for the high morbidity/mortality associated diseases (ATL and HAM/TSP) are limited, therefore, infection prevention is of utmost importance. However, antenatal screening is not routinely performed in Brazil. A lack of data regarding the number of individuals infected via breastfeeding impairs the development of government policies. The objective is to estimate the number of HTLV-1 infections occurring annually due to mother to child transmission (MTCT) in Brazil, nationally and regionally.MethodologyTo estimate HTLV-1 MTCT in Brazil the following variables are modelled: number of births, prevalence of HTLV-1 infection in pregnant women, breastfeeding duration rate and transmission risk according to breastfeeding period. The number of cases of HAM/TSP and ATL attributable to MTCT are also estimated.Principal findingsIn 2008, there were 2,934,828 live births in Brazil. HTLV prevalence in pregnant women in Brazil ranges between 0.1–1.05% by region. An estimated 16,548 HTLV-1 infected women are pregnant each year. According to the breastfeeding pattern and HTLV-1 prevalence of each region there are an estimated 3,024 new cases of HTLV-1 infection due to MTCT annually of which 2,610 are preventable through infant feeding advice. These 3,024 transmissions will result in 120–604 cases of ATL and 8–272 of HAM/TSP. North-East region comprises the high number of MTCT cases, followed by South-East.Conclusions/significanceA high number of new HTLV-1 infections due to MTCT occur every year in Brazil. Antenatal screening and avoiding breastfeeding are essential to prevent subsequent development of HTLV-1-associated diseases.

Revisiting human T-cell lymphotropic virus types 1 and 2 infections among rural population in Gabon, central Africa thirty years after the first analysis.

HTLV-1 infection is considered as highly endemic in central Africa. Thirty years ago, a first epidemiological study was performed in Gabon, central Africa, and revealed that the prevalence varied from 5.0 to 10.5%. To evaluate current distribution of HTLVs in Gabon, 4.381 samples were collected from rural population living in 220 villages distributed within the 9 provinces of country. HTLVs prevalence was determined using two ELISA tests and positive results were confirmed by Western Blot. The overall HTLV-1 seroprevalence was of 7.3% among the rural Gabonese population; with 5.4% for men and 9.0% for women. Prevalence of HTLV-1 differed by province, ranging from 2.3% to 12.5% into the rain forest. Being a woman older than 51 years represented a high risk for HTLV-1 acquisition. Hospitalization, operation/surgery, transfusion and medical abortion or fever, arthritis and abdominal pain are also significant risk factors. In addition, 0.1% of samples were found as HTLV-2 positive, while 12.0% had an indeterminate HTLV serological pattern. HTLV-3 and HTLV-4 were not found. Phylogenetic analysis was performed on 87 samples and demonstrated that HTLV-1 present in Gabon belongs mostly to subtype B, however the rare subtype D was also found. Altogether, our results demonstrate that almost thirty years after the first epidemiological study prevention of HTLVs infection is still an issue in Gabon.

Different roles of CXCR1 and CXCR2 in HTLV-1 carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients.

One of the prominent features of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the excessive recruitment of leukocytes to the central nervous system (CNS), which leads to an inflammatory response-with chemokines and their receptors playing the main role in this recruitment. The aim of the study was to examine the relation of CXCR1 and CXCR2, both of which are involved in the trafficking of lymphocytes into the CNS, with the outcome of HTLV-1 infection. The mRNA levels of CXCR1 and CXCR2 were examined in peripheral blood mononuclear cells (PBMCs) of HAM/TSP patients, HTLV-1 asymptomatic carriers (ACs), and healthy controls (HCs). Furthermore, the frequency of CD4+ and CD8+ T cells expressing CXCR1 and CXCR2 was evaluated in the studied groups. The results of the present study showed a substantial increase in the mean mRNA expression of CXCR2 in the HAM/TSP patients compared to the HCs and ACs (p < 0.001). A positive correlation was also found between PVL and CXCR2 mRNA expression in the total population of HTLV-1-infected subjects (R = 0.526, p < 0.001). Moreover, the percentage of CD8+ CXCR2-expressing cells was higher in HAM/TSP patients compared to ACs and HCs (p < 0.05, p < 0.01, respectively). Although the percentage of CD4+ CXCR2-expressing cells was higher in HAM/TSP patients than in ACs and HCs, a significant difference was only found between HAM/TSP patients and HCs (p < 0.05). No significant difference in the CXCR1 mRNA expression was observed in the studied groups. The frequency of the CD8+ CXCR1- and CD4+ CXCR1-expressing cells was significantly lower in HAM/TSP patients than in ACs and HCs (p < 0.001 and p < 0.01, respectively). In conclusion, the high frequency of CXCR2 CD8+ T cells and the high levels of CXCR2 mRNA expression in HAM/TSP patients are associated with disease pathogenesis, while the high frequencies of CXCR1 T cells in ACs might suggest that these cells act as effector CD8 T cells and are involved in controlling the viral spread and modulation of the immune response.

Moderate endemicity of the human T-lymphotropic virus infection in the metropolitan region of Belém, Pará, Brazil.

The spread of the HTLV infection in families living in the metropolitan area of Belém, Pará, Brazil, and the lack of studies in the general population requires studies to better understand its prevalence in the region. An anti-HTLV-1/HTLV-2 antibodies test was carried out on random adults in public places in Belém between November 2014 and November 2015. A proviral DNA test detected if the person was infected, and then a clinical evaluation and an intrafamilial investigation were carried out. Of the 1059 individuals being investigated, 21 (2.0%) had seroreagent samples, 15 (1.4%) had HTLV-1, 5 (0.5%) had HTLV-2, and proviral DNA was undetectable in one case. The mean age of the infected people (57.2) was higher than that of those that were uninfected (46.2) (p = 0.0010). The prevalence of infection increased with age, especially in individuals with a family income equal to or less than a minimum wage. Intrafamilial transmission seems to have occurred in all of the families being studied. Among the patients with HTLV-1, 30% (3/10) already had some symptom related to the infection. The increase in prevalence rates according to age may be due to late seroconversion of a previously acquired infection, or the cumulative risk of new infections, especially in women. There was a moderate prevalence of the HTLV infection among adult individuals from the metropolitan area of Belém, with a predominance of HTLV-1. This infection was associated with low income and increasingly older women. It also presented intrafamily spread and negligence in the diagnosis of associated diseases.

Is there any association between human T-lymphotropic virus type 1 (HTLV-1) infection and Behcet’s disease?

Both human T-cell lymphotropic virus type 1 (HTLV-1) infection and Behcet’s disease (BD) are common to a similar geographic area. Furthermore, some clinical presentations of BD and HTLV-1 infection, such as ocular lesions and neurologic involvement, are the same. The aim of this study was to assess a possible association between BD and HTLV-1 infection.In this case-control study, the HTLV-1 infection frequency in BD patients was compared with that for the general population. The case group consisted of 68 patients with a definite diagnosis of BD who referred to a research center at Mashhad University of Medical Sciences in Mashhad, Iran. The control group consisted of 210 healthy individuals selected from the general population of Mashhad. The presence of HTLV antibodies in the sera was assessed using enzyme-linked immunosorbent assay and the seroreactive samples were confirmed by polymerase chain reaction.HTLV-1 infection was detected in 4.41% (3/68) and 1.43% (3/210) of cases and controls, respectively; however, the difference was not statistically significant (P value = 0.16).The prevalence of HTLV1 infection in patients with BD was three-fold higher than in the general population, which suggests an association between these two conditions.

HTLV-1 infection-induced motor dysfunction, memory impairment, depression, and brain tissues oxidative damage in female BALB/c mice

AimsThe HTLV-1 infection is associated with a neuro-inflammatory disease. In the present study, the behavioral consequences and brain oxidative damages were evaluated in HTLV-1-infected BALB/c mice. Material and methods20 female BALB/c mice were divided into two groups comprising control and HTLV-1-infected. The HTLV-1-infected group was inoculated with a 106 MT-2 HTLV-1-infected cell line. Two months later, the behavioral tests were conducted. Finally, oxidative stress was assessed in the cortex and hippocampus tissues. Key findingsIn the HTLV-1-infected group, running time and latency to fall, travel distance and time spent in the peripheral zone, total crossing number and total traveled distance in open field test, the latency of entrance into the dark compartment in the passive avoidance test, the new object exploration percentage, and discrimination ratio were significantly lower than in the control group. The immobility time, time spent in the dark compartment in passive avoidance test, and total exploration time significantly increased in the HTLV-1-infected group compared to the control group. In the cortical tissue of the HTLV-1 group, the malondialdehyde levels were elevated while the total thiol levels decreased in comparison to the control group. The activity of superoxide dismutase in the cortical and hippocampal tissues, and catalase activity in cortical tissue significantly decreased in the HTLV-1 group in comparison to the control group. SignificanceThe HTLV-1 infection seems to induce depression-like behavior, motor dysfunction, disruption in working and fear memory and also oxidative stress in the cortex and hippocampus.

Isolated Neurogenic Bladder Associated With Human T-Lymphotropic Virus Type 1 Infection in a Renal Transplant Patient From Central Australia: A Case Report

BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) is endemic amongst the Aborigines of the Northern Territory of Australia. HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) has been associated with this infection. In general population, isolated neurogenic bladder dysfunction in HTLV-1-infected individuals without HAM/TSP has been reported, and the HTLV-1 proviral load has been found to be higher in such patients compared with asymptomatic carriers. In solid organ transplantation, few cases of HAM/TSP have been reported worldwide, but not an isolated neurogenic bladder. CaseA 50-year-old indigenous women from Alice Springs with end stage renal disease secondary to diabetic nephropathy with no prior history of bladder dysfunction received a cadaveric renal allograft following which she developed recurrent urinary tract infections. The recipient was seropositive for HTLV-1 infection. HTLV-1 status of donor was not checked. Urodynamic studies revealed stress incontinence and detrusor overactivity without urethral intrinsic sphincter deficiency. She had no features of myelopathy. There was elevation of the serum and cerebrospinal fluid HTLV-1 proviral load. The magnetic resonance imaging myelogram was normal. Pyelonephritis was diagnosed based on clinical features, positive cultures, and renal allograft biopsy. Continuous suprapubic catheter drainage helped preventing further episodes of allograft pyelonephritis in spite of chronic colonization of the urinary tract. ConclusionIsolated bladder dysfunction is a rare manifestation of HTLV-1 infection and is probably associated with high proviral loads. This may adversely affect renal allograft and patient outcomes.

Human T-Lymphotropic Virus-1-Associated Myelopathy/Tropical Spastic Paraparesis Is Associated With Sexual Dysfunction in Infected Women of Reproductive Age.

IntroductionHuman T-lymphotropic virus (HTLV)-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disorder that mostly affects women. This disease is characterized by a progressive loss of motor function and disruptions in sensory function in the lower limbs. HTLV-1 is also associated with isolated neurologic dysfunctions, overactive bladder, and erectile dysfunction. The occurrence of sexual dysfunction in HTLV-1–infected women remain unclear.AimTo investigate associations between HTLV-1 infection and sexual dysfunction in both asymptomatic infected women and those diagnosed with HAM/TSP compared with uninfected women.MethodsHTLV-1–infected and uninfected women were assessed for sexual dysfunction using the Female Sexual Function Index instrument. Sexual dysfunction was considered if global Female Sexual Function Index scores were <26.5. Crude and adjusted prevalence ratios (PR) with 95% CI were calculated to identify associations between sexual dysfunction (outcome) and HTLV infection status–asymptomatic or HAM/TSP (main exposure), compared with uninfected women, and adjusted by sociodemographic and/or clinical characteristics (covariables).ResultsHTLV-1–infected women (n = 72; 57 asymptomatic; 15 HAM/TSP) and HTLV-1 uninfected women (n = 49) were evaluated. The overall sexual dysfunction prevalence was 53.7% (65/121), which was higher in the HAM/TSP group (80.0%; adjusted PR 1.89; 95% CI 1.23–2.90) when compared with non-infected individuals (44.9%). Sexual dysfunction was found in 54.4% of the HTLV-1–infected asymptomatic women (PR 1.21; 95% CI 0.82–1.79). Sexual dysfunction was associated with income lower than 1 minimal wage (∼US $300, October 2017) and number of previous birthday.ConclusionThe obtained results indicate that sexual dysfunction is associated with HAM/TSP in women infected with HTLV-1 of reproductive age.Lima Lopes Martins A, Rios Grassi MF, de Aquino Firmino A, et al. Human T-Lymphotropic Virus-1–Associated Myelopathy/Tropical Spastic Paraparesis Is Associated With Sexual Dysfunction in Infected Women of Reproductive Age. Sex Med 2018;6:324–331.

Meta-analysis of correlationship between HLA-G 3'UTR 14-bp Ins/Del polymorphism and virus susceptibility.

Background:There is a considerable amount of literature on the potential relationship between human leukocyte antigen-G 14-bp Ins/Del polymorphism and virus infection; however, results from these studies were inconclusive.Objectives:A meta-analysis was carried out to determine whether the 14-bp Ins/Del polymorphism is a susceptible factor for virus infection.Methods:Data were extracted from PubMed and Web of Science databases, and included 10 case–control studies (1835 patients and 2357 controls).Results:A total of 177 records from 10 studies were retrieved. Overall, no significant correlation was found between HLA-G 14-bp Ins/Del polymorphism and total viruses under all genetic models (dominant model: OR = 0.93, 95% CI = 0.68–1.29; recessive model: OR = 1.12, 95% CI = 0.84–1.48; deletion/deletion (DD) vs insertion/insertion (II): OR = 1.03, 95% CI = 0.71–1.49; deletion (D) vs insertion (I): OR = 1.01, 95% CI = 0.81–1.25). However, further subgroup analyses by virus type and ethnicity revealed that HLA-G 14-bp Ins/Del polymorphism was significantly associated with HTLV-1 infection in mixed population under the dominant model.Conclusions:Our study demonstrated that HLA-G 14-bp Ins/Del polymorphism may not have any effect on susceptibility to viruses.

Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes

BackgroundHTLV-1 infects over 20 million people worldwide and causes a progressive neuroinflammatory disorder in a subset of infected individuals called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The detection of HTLV-1 specific T cells in the cerebrospinal fluid (CSF) suggests this disease is immunopathologically mediated and that it may be driven by viral antigens. Exosomes are microvesicles originating from the endosomal compartment that are shed into the extracellular space by various cell types. It is now understood that several viruses take advantage of this mode of intercellular communication for packaging of viral components as well. We sought to understand if this is the case in HTLV-1 infection, and specifically if HTLV-1 proteins can be found in the CSF of HAM/TSP patients where we know free virus is absent, and furthermore, if exosomes containing HTLV-1 Tax have functional consequences.ResultsExosomes that were positive for HTLV-1 Tax by Western blot were isolated from HAM/TSP patient PBMCs (25/36) in ex vivo cultures by trapping exosomes from culture supernatants. HTLV-1 seronegative PBMCs did not have exosomes with Tax (0/12), (Fisher exact test, p = 0.0001). We were able to observe HAM/TSP patient CSF (12/20) containing Tax+ exosomes but not in HTLV-1 seronegative MS donors (0/5), despite the absence of viral detection in the CSF supernatant (Fisher exact test p = 0.0391). Furthermore, exosomes cultivated from HAM/TSP PBMCs were capable of sensitizing target cells for HTLV-1 specific CTL lysis.ConclusionCumulatively, these results show that there are HTLV-1 proteins present in exosomes found in virus-free CSF. HAM/TSP PBMCs, particularly CD4+CD25+ T cells, can excrete these exosomes containing HTLV-1 Tax and may be a source of the exosomes found in patient CSF. Importantly, these exosomes are capable of sensitizing an HTLV-1 specific immune response, suggesting that they may play a role in the immunopathology observed in HAM/TSP. Given the infiltration of HTLV-1 Tax-specific CTLs into the CNS of HAM/TSP patients, it is likely that exosomes may also contribute to the continuous activation and inflammation observed in HAM/TSP, and may suggest future targeted therapies in this disorder.

First detection of human T‐lymphotropic virus in blood donors in Benin shows that testing is required to improve blood safety

IntroductionHuman T‐lymphotropic virus (HTLV) is a blood‐borne infection that can be transmitted via blood transfusion. Knowing that blood safety can improve blood transfusion to prevent dissemination of viral infections in medical facilities, there is no routine pre‐transfusion screening for HTLV in all blood banks in the Republic of Benin. This study aims to estimate the prevalence of HTLV infection in blood donors and describes the characteristics of positive donors.MethodsA HTLV prevalence study was carried out by screening 2,035 samples by an enzyme‐linked immunoassay obtained from six blood banks located throughout the Republic of Benin. The PCR method was used to confirm and type all the ELISA reactive samples.Results and discussionTwelve subjects, all volunteer blood donors, were found with positive serology confirmed by a specific HTLV type 1 PCR assay, representing an overall seroprevalence of 0·59%. Furthermore, seven subjects were indeterminate for anti‐HTLV‐1/2 antibody and only one sample was confirmed positive for HTLV type 1 in a PCR reaction. These are the first cases of HTLV detection among blood donors in Benin Republic, whose blood was already transfused to recipients. This result emphasizes that HTLV needs to be considered as a Public Health issue in the Republic of Benin.ConclusionThis study reports positive result of HTLV infection among blood donors in the blood banks of Benin Republic in West Africa and highlights the inclusion of screening tests and strategies to reduce its transmission.

Serological detection of human T-cell lymphotropic virus types I and II among pregnant women in Ilorin, Nigeria

ABSTRACTHuman T-cell lymphotropic virus types I/II (HTLV-I/II) is endemic in some parts of the world including Nigeria. Reported prevalence rates in Nigeria have largely focused on blood donors. This study aims at determining the prevalence of HTLV infection among pregnant women in Ilorin North-central Nigeria. Serum samples from 276 pregnant women who were antenatal clinic attendees at General and Civil Service Hospitals in Ilorin were tested for the presence of HTLV-I/II antibodies using Enzyme Linked Immunosorbent Assay test kits from Diagnostic Automation INC., USA. Out of the 276 women tested, 3 tested positive giving a prevalence rate of 1.1%. The result was analyzed on the basis of age, marital status, nature of family, educational status, occupation, religion, parity, and gestational stage of the women. There was no statistical association of HTLV positivity with any of the variables. Although relatively lower than prevalence rate recorded among similar study groups in other parts of the country, the 1.1% prevalence in this study underscores the need for proper education and creation of awareness among antenatal clinic attendees, so as to reduce viral transmission and incidence of HTLV-related diseases.

Low prevalence of HTLV1/2 infection in a population of immigrants living in southern Italy.

AimsTo assess the prevalence of HTLV-1 and HTLV-2 infections in a cohort of immigrants living in southern Italy.FindingsWe screened for antibody to HTLV-1/2 infection 1,498 consecutive immigrants born in endemic areas (sub-Saharan Africa or southern-Asia) by a commercial chemiluminescent microparticle immunoassay. If confirmed in a Western blot assay, which differentiates anti-HTLV-1 from anti-HTLV-2, the positive sera were tested for specific HTLV RNA by a home-made PCR. The immigrants investigated were more frequently males (89.05%), young (median age 26 years), with a low level of education (median schooling 6 years), born in sub-Saharan Africa (79.70%). They had been living in Italy for a median period of 5 months. Only one (0.07%) subject was anti-HTLV-1 -positive/HTLV-1 RNA-negative; he was an asymptomatic 27-year-old male from Nigeria with 6 years’ schooling who stated unsafe sexual habits and unsafe injection therapy.ConclusionsThe data suggest screening for HTLV1 and HTLV-2 infections all blood donors to Italy from endemic countries at least on their first donation; however, a cost-effectiveness study is needed to clarify this topic.

HTLV-1 and -2 in a first-time blood donor population in Northeastern Brazil: Prevalence, molecular characterization, and evidence of intrafamilial transmission.

Independent epidemiology for respective human T-cell lymphotropic virus (HTLV) types 1 and 2 is little known in blood donors in Brazil, where screening for HTLV-1/2 is mandatory at blood banks, but no testing to confirm/differentiate these viruses. Therefore, this study aims to assess the prevalence of HTLV-1 and -2 in a first-time blood donor population in Northeastern Brazil and to carry out molecular characterization of respective isolates. A cross-sectional study was conducted at the State Blood Bank in Piauí. Samples were screened for anti-HTLV-1/2 by enzyme immunoassay, and reactive samples were confirmed using a line immunoassay and polymerase chain reaction (PCR). Of 37 306 blood donors, 47 were anti-HTLV-1/2 reactive by enzyme immunoassay. After confirmed by line immunoassay, 22 were positive for HTLV-1 (0.59 per 1000; 95% CI: 0.38-0.87), 14 were positive for HTLV-2 (0.37 per 1000; 95% CI: 0.21-0.61), 1 was indeterminate, and the remaining donors were negative. The HTLV-1 infection was also confirmed by PCR in all anti-HTLV-1-positive samples, and sequencing classified these isolates as belonging to the Transcontinental (A) subgroup of the Cosmopolitan (1a) subtype. Of 14 anti-HTLV-2-positive samples, 11 were also PCR positive, which belonged to subtype a (HTLV-2a/c). In addition, 38 family members of 5 HTLV-1- and 3 HTLV-2-infected donors were analyzed. Familial transmission of HTLV-1 and -2 was evidenced in 3 families. In conclusion, in Northeastern Brazil, where HTLV-1 and -2 are endemic, counseling blood donor candidates and their families might play a key role in limiting the spread of these viruses.

IFNG +874A/T Polymorphism Among Asymptomatic HTLV-1-Infected Individuals Is Potentially Related to a Worse Prognosis.

HTLV-1 infections are persistent and frequently latent; however, productive infections trigger different types of immunological responses that utilize cytokines to control infection. The present study investigated the role of IFNG +874A/T polymorphisms among 153 HTLV-1-infected individuals (33 clinically diagnosed with TSP/HAM, 22 with rheumatologic manifestations, 2 with dermatitis, 1 with uveitis, and 95 asymptomatic patients) and 300 healthy control individuals. Genotyping and proviral HTLV-1 load assessment were performed using real-time PCR assays, and the plasma levels of IFN-γ were measured using an enzyme immunoassay (ELISA). Genotype frequencies were not significantly different, but the presence of the T allele was higher (p < 0.0142) among the asymptomatic patients. Plasma levels of IFN-γ were significantly higher (p < 0.0137) among those with the TT genotype. Their proviral load was also higher, although this elevation did not reach statistical significance. There was no difference in the IFN-γ plasma levels among the symptomatic patients, even when ranked according to disease severity (TSP/HAM or rheumatologic manifestations). However, the difference among asymptomatic patients with the T allele was significantly higher (p < 0.0016) and similar to the plasma levels observed among symptomatic individuals. These results suggest that the IFNG +874A/T polymorphism may modulate the plasma levels of IFN-γ during HTLV-1 infection. Asymptomatic carriers of the polymorphic genotypes appear to develop an inflammatory response in a shorter timeframe, triggering progression to HTLV-1-related symptoms and disorders. These results further suggest that HTLV-1-infected asymptomatic individuals expressing the IFNG +874A/T polymorphism should be monitored more closely in order to readily detect the increase in clinical symptoms, as these patients are potentially at risk of a poor prognosis and should therefore start available treatment procedures earlier.

Risk factors associated with HTLV-1 vertical transmission in Brazil: longer breastfeeding, higher maternal proviral load and previous HTLV-1-infected offspring

HTLV-1 is transmitted primarily either through sexual intercourse or from mother to child. The mother/child pairs were classified as seroconcordant or serodiscordant. We analyzed mother to child transmission (MTCT) according to sociodemographic, clinical and epidemiological characteristics of the mother, child’s gender and duration of breastfeeding. Between June 2006 and August 2016 we followed 192 mothers with HTLV-1 infection (mean age 41 years old), resulting in 499 exposed offspring, 288 (57.7%) of whom were tested for HTLV-1, making up the final sample for the study, along with their 134 respective mothers. Among the tested mother/child pairs, 41 (14.2%) were HTLV-1 positive, highlighted that seven of 134 family clusters concentrated 48.8% of positive cases. Variables associated with a positive child: breastfeeding duration ≥12 months, maternal PVL ≥100 copies/104 PBMC, mother’s age at delivery >26 years old, and HTLV-1 in more than one child of the same mother. In a multiple logistic regression, breastfeeding ≥12 months, higher maternal PVL and ≥2 previous HTLV-1-infected children remained independently associated with the outcome. Thus, high maternal PVL and breastfeeding beyond 12 months were independently associated with MTCT of the HTLV-1 infection. Our results reinforce the need for both prenatal HTLV screening in endemic areas and for advising mothers on breastfeeding.

Detection of HTLV-1 proviral DNA in BM mononuclear cells and cultured mesenchymal stromal cells isolated from patients with HTLV-1 infection

The bone marrow (BM) biology during HTLV-1 infection is obscure. In this study, we investigated BM mononuclear cells and mesenchymal stromal cells (MSC) from HTLV-1 asymptomatic and symptomatic individuals. An infiltration of CD4+ T-cell lymphocytes in the BM of HTLV-1-infected individuals was observed when compared to healthy controls. The provirus detection in the BM CD4+ T cells confirmed the presence of integrated HTLV DNA. In regard to MSC, we observed that the number of fibroblast progenitor cells was lower in HTLV-1 infected individuals than in healthy controls. Isolated HTLV-1 infected BM-MSC demonstrated surface expression markers and in vitro differentiation potential similar to uninfected individuals. The presence of HTLV-1 proviral DNA in the BM-MSC of HTLV-1-infected patients was demonstrated but no p19 antigen was detected in supernatant from cultured MSC. We suppose that HTLV-1 infects human MSC probably by cell-to-cell contact from the infected CD4+ T-lymphocytes infiltrated into the bone marrow.

Temporal trends in Human T-Lymphotropic virus 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP) incidence in Martinique over 25 years (1986-2010).

BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) has been discovered in 1980 and has been linked to tropical spastic paraparesis (HAM/TSP) in 1985 in Martinique. There is no data on HAM/TSP incidence trends. We report, in the present work, the temporal trends incidence of HAM/TSP in Martinique over 25 years.MethodsMartinique is a Caribbean French West Indies island deserved by a unique Neurology Department involved in HAM/TSP diagnosis and management. A registry has been set up since 1986 and patients diagnosed for a HAM/TSP were prospectively registered. Only patients with a definite HAM/TSP onset between 1986 and 2010 were included in the present study. The 25-year study time was stratified in five-year periods. Crude incidence rates with 95% confidence interval (95%CI) were calculated using Poisson distribution for each period. Age-standardized rates were calculated using the direct method and the Martinique population census of 1990 as reference. Standardized incidence rate ratios with 95% CIs and P trends were assessed from simple Poisson regression models. Number of HTLV-1 infection among first-time blood donors was retrospectively collected from the central computer data system of the Martinique blood bank. The HTLV-1 seroprevalence into this population has been calculated for four 5-year periods between 1996 and 2015.ResultsOverall, 153 patients were identified (mean age at onset, 53+/-13.1 years; female:male ratio, 4:1). Crude HAM/TSP incidence rates per 100,000 per 5 years (95%CI) in 1986–1990, 1991–1995, 1996–2000, 2001–2005 and 2006–2010 periods were 10.01 (6.78–13.28), 13.02 (9.34–16.70), 11.54 (8.13–14.95), 4.27 (2.24–6.28) and 2.03 (0.62–3.43). Age-standardized 5-year incidence rates significantly decreased by 69% and 87% in 2001–2005 and 2006–2010 study periods. Patients characteristics did not differ regarding 1986–2000 and 2001–2010 onset periods. Between 1996–2000 and 2011–2015 study periods, the HTLV-1 seroprevalence significantly decreased by 63%.ConclusionMartinique faces a sudden and rapid decline of HAM/TSP incidence from 2001 in comparison to 1986–2000 periods. Reduction of HTLV-1 seroprevalence, that may result from transmission prevention strategy, could account for HAM/TSP incidence decrease.

Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians.

BackgroundThe Human T-Lymphotropic Virus type 1c subtype (HTLV-1c) is highly endemic to central Australia where the most frequent complication of HTLV-1 infection in Indigenous Australians is bronchiectasis. We carried out a prospective study to quantify the prognosis of HTLV-1c infection and chronic lung disease and the risk of death according to the HTLV-1c proviral load (pVL).Methodology/Principal findings840 Indigenous adults (discharge diagnosis of bronchiectasis, 154) were recruited to a hospital-based prospective cohort. Baseline HTLV-1c pVL were determined and the results of chest computed tomography and clinical details reviewed. The odds of an association between HTLV-1 infection and bronchiectasis or bronchitis/bronchiolitis were calculated, and the impact of HTLV-1c pVL on the risk of death was measured.Radiologically defined bronchiectasis and bronchitis/bronchiolitis were significantly more common among HTLV-1-infected subjects (adjusted odds ratio = 2.9; 95% CI, 2.0, 4.3). Median HTLV-1c pVL for subjects with airways inflammation was 16-fold higher than that of asymptomatic subjects. There were 151 deaths during 2,140 person-years of follow-up (maximum follow-up 8.13 years). Mortality rates were higher among subjects with HTLV-1c pVL ≥1000 copies per 105 peripheral blood leukocytes (log-rank χ2 (2df) = 6.63, p = 0.036) compared to those with lower HTLV-1c pVL or uninfected subjects. Excess mortality was largely due to bronchiectasis-related deaths (adjusted HR 4.31; 95% CI, 1.78, 10.42 versus uninfected).Conclusion/SignificanceHigher HTLV-1c pVL was strongly associated with radiologically defined airways inflammation and with death due to complications of bronchiectasis. An increased risk of death due to an HTLV-1 associated inflammatory disease has not been demonstrated previously. Our findings indicate that mortality associated with HTLV-1c infection may be higher than has been previously appreciated. Further prospective studies are needed to determine whether these results can be generalized to other HTLV-1 endemic areas.

A genetic IFN/STAT1/FAS axis determines CD4 T stem cell memory levels and apoptosis in healthy controls and Adult T-cell Leukemia patients

ABSTRACTAdult T-cell leukemia (ATL) is an aggressive, chemotherapy-resistant CD4+CD25+ leukemia caused by HTLV-1 infection, which usually develops in a minority of patients several decades after infection. IFN + AZT combination therapy has shown clinical benefit in ATL, although its mechanism of action remains unclear. We have previously shown that an IFN-responsive FAS promoter polymorphism in a STAT1 binding site (rs1800682) is associated to ATL susceptibility and survival. Recently, CD4 T stem cell memory (TSCM) Fashi cells have been identified as the hierarchical cellular apex of ATL, but a possible link between FAS, apoptosis, proliferation and IFN response in ATL has not been studied.In this study, we found significant ex vivo antiproliferative, antiviral and immunomodulatory effects of IFN-α treatment in short-term culture of primary mononuclear cells from ATL patients (n = 25). Bayesian Network analysis allowed us to integrate ex vivo IFN-α response with clinical, genetic and immunological data from ATL patients, thereby revealing a central role for FAS -670 polymorphism and apoptosis in the coordinated mechanism of action of IFN-α. FAS genotype-dependence of IFN-induced apoptosis was experimentally validated in an independent cohort of healthy controls (n = 20). The same FAS -670 polymorphism also determined CD4 TSCM levels in a genome-wide twin study (p = 7 × 10−11, n = 460), confirming a genetic link between apoptosis and TSCM levels. Transcriptomic analysis and cell type deconvolution confirmed the FAS genotype/TSCM link and IFN-α-induced downregulation of CD4 TSCM-specific genes in ATL patient cells.In conclusion, ex vivo IFN-α treatment exerts a pleiotropic effect on primary ATL cells, with a genetic IFN/STAT1/Fas axis determining apoptosis vs. proliferation and underscoring the CD4 TSCM model of ATL leukemogenesis.