Immunological response, Viral Factors and Helminth Infections in Disease Expressi

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DESCRIPTION (provided by applicant): The human T cell lymphotropic virus type 1 (HTLV-1) infects 20 million individuals worldwide and is the causal agent of HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Salvador-Ba, Brazil has the highest prevalence of HTLV-1 infection in the country. In the last 10 years, with the participation of a multidisciplinary team and in collaboration with NIH researchers and faculty of Cornell University, we have characterized immunological responses in HTLV-1 carriers and in patients with HAM/TSP and determined the basis of the immunological changes that increase the susceptibility of HTLV-1 infected subjects to development of disseminated strongyloidiasis. More recently, under the support of an R03 "Immunological Response and Disease Expression in HTLV-1" awarded by the NIH, we documented that neurological and joint manifestations, periodontitis, sicca syndrome, urinary manifestations and erectile dysfunction were higher among HTLV-1 carriers than in seronegative controls. Moreover, we described cases of HTLV-1-associated neurogenic bladder among individuals who do not fulfill the criteria for HAM/TSP and showed that this sign could be an early manifestation of HAM/TSP. The present proposal, entitled Immunological response, Viral Factors and Helminth Infections in Disease Expression Associated with HTLV-1 Infection, extends our previous studies to determine: 1) The natural history of HTLV-1 infection; 2) Host immunological and viral factors associated with disease expression; and 3) The influence of helminths in the immune response and in the clinical outcome of HTLV-1 infection. Using a cohort of 500 asymptomatic HTLV-1 carriers, the following clinical outcomes will be measured: neurogenic bladder associated with HTLV-1, HAM/TSP, and worsening of neurological manifestations. These outcomes will also be compared in patients with and without helminth infection. The influence of immunological responses and viral factors in disease expression will be determined in a cross-sectional study with three groups of patients: 1) Patients with neurogenic bladder associated with HTLV-1; 2) Patients with HAM/TSP; and 3) Patients with asymptomatic HTLV-1 infection. We will determine levels of pro-inflammatory cytokines (TNF-, IFN-, IL-17), chemokines that attract T cells to inflammatory sites (CXCL9, CXCL10), the frequency of CD8 T cells expressing IFN- and TNF- and of cytokines and cells that down-modulate immunological response (IL-10, IL-27 regulatory T cells). Proviral load will be measured and viral DNA will be stored for future studies aimed at evaluating viral polymorphisms that could be associated with HAM/TSP. PUBLIC HEALTH RELEVANCE: Very little is known about clinical manifestations associated with HTLV-1, and as only 5% of HTLV-1-infected individuals develop myelopathy (HAM/TSP), HTLV-1 is considered a low morbidity infection. In this study evaluating prospectively a cohort of 500 HTLV-1 infected subjects, we will have the opportunity to describe aspects of the natural history of HTLV-1 infection and to show that clinical and neurological manifestations associated with HTLV-1 occur in a large proportion of infected subjects. Moreover, as helminths are endemic in Salvador-Bahia and it has been widely shown that helminths can attenuate clinical manifestations of chronic inflammatory and auto-immune diseases, we will determine the influence of helminth infection on clinical manifestations related to HTLV-1 Northeastern Brazil. Furthermore, we intend to identify a correlation between immunological response and viral factors with disease expression in HTLV-1 infection. This study will allow us Identify neurological manifestations in an early phase of the disease, when potential interventions may prevent neurological damage and improve recovery of neurological function.