Neurologic, clinical, and immunologic features in a cohort of HTLV-1 carriers with high proviral loads

Sheila N Ferraz,Lívia M A Oliveira,Mariele Guerra,Gabriela F Costa,José Abraão Carneiro Neto,Edgar M Carvalho,Cassius J V De Oliveira,Thiago Hebert

doi:10.1007/s13365-020-00847-y

Abstract

A high proviral load (PVL) is recognized as a risk factor for human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but there is a lack of prospective studies evaluating whether or not HTLV-1 carriers with high PVL are at risk of developing HAM/TSP or other HTLV-1-related diseases. Here, we compare the incidence of clinical manifestations and the cytokine levels in 30 HTLV-1 carriers with high (> 50,000 copies/106 PBMC) and an equal number of subjects with low proviral load. Participants were followed for 3 to 16 years (median of 11 years). The PVL, IFN-γ, TNF, and IL-10 levels were quantified at entry and at the end of the follow-up. Among the self-reported symptoms in the initial evaluation, only the presence of paresthesia on the hands was more frequent in the group with high PVL (p < 0.04). The production of IFN-γ was higher in the group with high PVL group (median of 1308 versus 686 pg/ml, p < 0.011) when compared with the control group in the first assessment. There was no difference in the occurrence of urinary symptoms or erectile dysfunction, periodontal disease, Sicca syndrome, and neurologic signs between the two groups during the follow-up. The observation that none of the HTLV-1 carriers with high PVL and with exaggerated inflammatory response progressed to HAM/TSP indicates that other factors in addition to the PVL and an exaggerated immune response are involved in the pathogenesis of HAM/TSP.

Highlights

The human T cell leukemia virus-1 (HTLV-1) was the first human retrovirus to be described (Poiesz et al 1980) and is the etiologic agent of adult T cell leukemia/lymphoma (ATL) (Uchiyama et al 1977) and HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP) (Osame et al 1986; Gessain et al 1985)
The HAM/TSP only occurs in less than 5% of HTLV-1infected subjects (Gessain and Mahieux 2012), but there are other clinical manifestations associated with this virus such as ATL (Poiesz et al 1980), Sicca syndrome (Lima et al 2016), periodontal disease (Garlet et al 2010), and arthropathy (Frenzel et al 2014)
40% of the HTLV-1infected subjects without HAM/TSP have neurologic symptoms and signs related to spinal cord involvement, such as paresthesia, weakness in the inferior limbs, difficult walking, urologic manifestations of neurogenic bladder, and erectile dysfunction (Tanajura et al 2015; Biswas et al 2009; Poetker et al 2011; Caskey et al 2008)

Summary

Introduction

The human T cell leukemia virus-1 (HTLV-1) was the first human retrovirus to be described (Poiesz et al 1980) and is the etiologic agent of adult T cell leukemia/lymphoma (ATL) (Uchiyama et al 1977) and HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP) (Osame et al 1986; Gessain et al 1985). The HTLV-1 virus preferentially infects CD4 T cells but is found in CD8 T cells, B cells, and dendritic cells (Bangham 2018; Martin et al 2016). HTLV-1 infection activates genes that induce T cell proliferation and. About 20% of individuals infected with HTLV-1 without HAM/TSP have urinary dysfunctions, especially due to overactive bladder (Troisgros et al 2017). Erectile dysfunction is observed in more than 40% of virus-infected subjects (de Oliveira et al 2017). In addition to the aforementioned diseases, individuals infected with HTLV-1 have more chronic periodontitis, Sicca syndrome, and arthropathy than seronegative individuals (Motokawa et al 1996; Poetker et al 2011; Caskey et al 2008)

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Conclusion