Altered Host Immunity, Human T Lymphotropic Virus Type I Replication, and Risk of Adult T-Cell Leukemia/Lymphoma: A Prospective Analysis from the ATL Cohort Consortium

Background: Adult T-cell leukemia/lymphoma (ATL) is a rare and often fatal outcome of infection with human T-lymphotropic virus type I (HTLV-I). Altered host immunity in HTLV-I carriers has been postulated as a risk factor for ATL, but is not well understood. Methods: We prospectively examined well-validated serologic markers of HTLV-I pathogenesis and host immunity in 53 incident ATL cases and 150 carefully matched asymptomatic HTLV-I carriers from eight population-based studies in Japan, Jamaica, the United States and Brazil. We used multivariable conditional logistic regression, conditioned on the matching factors (cohort/race, age, sex, and sample collection year), to evaluate the biomarkers’ associations with ATL in all subjects and by years (≤5, >5) from blood draw to ATL diagnosis. Results: In the pooled population, above-median soluble interleukin-2-receptor-alpha levels (sIL2R, v. ≤ median; odds ratio (OR), 95% confidence interval (CI)=4.08, 1.47-11.29) and anti-Tax seropositivity (anti-Tax; OR, 95% CI=2.97, 1.15-7.67), which indicate T cell activation and HTLV-I replication, respectively, were independently associated with an increased ATL risk. Above-median total immunoglobulin E levels (v. ≤ median; OR, 95% CI=0.45, 0.19-1.06), which indicate type 2 (B cell) activation, predicted a lower ATL risk. The sIL2R and anti-Tax associations with ATL were stronger in samples collected ≤5 years pre-diagnosis. Conclusions: The biomarker profile predictive of ATL risk suggests a role for heightened T cell activation and HTLV-I replication and diminished type 2 immunity in the etiology of ATL in HTLV-I carriers. Translation of these findings to clinical risk prediction or early ATL detection requires further investigation. Acknowledgements: This abstract is presented on behalf of the ATL Cohort Consortium

Testing the vestibular evoked myogenic potential (VEMP) to identify subclinical neurological alterations in different phases of human T-lymphotropic virus type 1 infection

BACKGROUND CONTEXT: The diagnosis of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is based on clinical signs and the confirmation of HTLV-1 infection in the central nervous system. Electrophysiological tests may facilitate an earlier diagnosis of spinal cord involvement. Vestibular evoked myogenic potential (VEMP) testing evaluates the vestibulospinal tract, which is correlated with the motor tract; the target of damage by HAM/TSP. PURPOSE: This study examines the subclinical neurological alterations related to HTLV-1 infection in individuals with asymptomatic HTLV-1 infections, possible HAM/TSP, and confirmed HAM/TSP. STUDY DESIGN: Vestibular evoked myogenic potential testing was performed at the beginning of the study and repeated every 6 months for 18 months. Ninety volunteers were selected for the study: 30 were HTLV-1 seronegative (the control group) and 60 were HTLV-1 seropositive (of these, 18 were asymptomatic, 25 had possible HAM/TSP, and 17 had confirmed HAM/TSP). The VEMP response was classified as normal or abnormal (latency prolongation or no response). A change in the VEMP response from normal to abnormal was the event of interest. To perform a survival analysis, the subjects with normal VEMP responses at the first assessment were selected. METHODS: The results were analyzed blindly. Vestibular evoked myogenic potential was measured using short tone bursts as acoustic stimuli (1 kHz, 118 dBHL, a rise-fall of 1 millisecond, and a plateau of 2 milliseconds). The stimulation rate was 5 Hz, and the analysis time for each response was 60 milliseconds; each trial averaged 200 responses. RESULTS: The mean age of the subjects in the control group was 38611 years (median 35), and 13 (43%) were men. In the study group, the mean age was 51612 years (median 53), and 12 (20%) were men. An analysis of the survival curve indicated that the median time for a change in VEMP response from normal to abnormal was 18 months, which is in agreement with the slow progression of HTLV-1-associated neurologic disease. The survival analysis showed that the change in VEMP response was significantly different between the asymptomatic and HAM/TSP groups (p=.02). CONCLUSIONS: Vestibular evoked myogenic potential testing was useful for monitoring the development of HAM/TSP in HTLV-1-infected individuals

Brain Metabolism Changes in Patients Infected with HTLV-1

The Human T-cell leukemia virus type-I (HTLV-1) is the causal agent of HTLV-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HAM/TSP is the result of demyelination and cell death in the spinal cord and disruption of the blood-brain barrier (BBB), mediated by a virus-induced inflammatory response. In this study, we applied Positron Emission Tomography with 18F-fluordeoxyglucose (18F-FDG PET) to evaluate brain metabolism in a group of 47 patients infected with HTLV-1, and 18 healthy controls. Patients were divided into three groups according to their neurological symptoms. A machine learning (ML) based Gaussian Processes classification algorithm (GPC) was applied to classify between patient groups and controls and also to organize the three patient groups, based on gray and white matter brain metabolism. We found that GPC was able to differentiate the HAM/TSP group from controls with 85% accuracy (p = 0.003) and the asymptomatic seropositive patients from controls with 85.7% accuracy (p = 0.001). The weight map suggests diffuse cortical hypometabolism in both patient groups when compared to controls. We also found that the GPC could separate the asymptomatic HTLV-1 patients from the HAM/TSP patients, but with a lower accuracy (72.7%, p = 0.026). The weight map suggests a diffuse pattern of lower metabolism in the asymptomatic group when compared to the HAM/TSP group. These results are compatible with distinctive patterns of glucose uptake into the brain of HTLV-1 patients, including those without neurological symptoms, which differentiate them from controls. Furthermore, our results might unveil surprising aspects of the pathophysiology of HAM/TSP and related diseases, as well as new therapeutic strategies