Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS) characterized by neuroinflammation, demyelination, and neuronal damage. MS is the most common autoimmune disease that affects the CNS, affecting > 2.5 million people worldwide (Walton et al., Dec. 2020). The average age at onset is 30 years old and prevalence according to geographic distribution and ethnicity. MS causes motor, sensory, autonomic, sensitive and cognitive disability, with severe functional impairment in young individuals (Kurtzke, 1995). The frequency of MS in Brazil is 1.36 / 100,000 to 27.2 / 100,000 inhabitants (Callegaro et al., 2001). Although the etiology of MS remains uncertain, clinical, epidemiological and laboratory findings suggest that environmental factors, and in particular one or more infectious agents, may be involved in the disease pathogenesis (Wolfson, 2001; Bar-Or et al., 2020).

MS is a disease that leads to the formation of focal plaques of primary demyelination and diffuse neurodegeneration in the white and gray matter of the brain and spinal cord (Lassmann et al., 2007). In most patients, the disease initiates with a relapsing-remitting course (RRMS), which is followed after several years by a secondary progressive phase (SPMS). About 50% of RRMS patients progressed to a SPMS phase within ten years of illness before the introduction of treatment era with disease-modifying drugs (DMS) in the 1990s, a frequency now just over 10% within 16 years of disease (University of California, San Francisco MS-EPIC Team et al., 2016). Patients with primary progressive disease (PPMS) begin with uninterrupted progression from the onset of the disease (Lublin and Reingold, 1996). Currently, anti-inflammatory or immunosuppressive therapies are beneficial in patients with RRMS (Wiendl and Hohlfeld, 2009), but effective in PPMS patients was approved with only one drug (Montalban et al., 2017).

MS is a disease of complex genetic inheritance, in which the phenotype is determined by the interaction of several genes with the environment (Küçükali et al., 2015). Of the many environmental contributors to the development of the disease, the immune trigger by viruses such as human T-cell lymphotropic virus type 1 (HTLV-1), Human coronavirus (HCoV), Human gammaherpesvirus 4 known as Epstein-Barr virus (EBV) (Warner and Carp, 1988; Oger, 2007; Boucher et al., 2007) and Human betaherpesvirus 6 also known Human herpesvirus-6 (HHV-6) (Alvarez-Lafuente et al., 2002) may play a role in the pathogenesis of the disease.

EBV and HHV-6 belong to the Herpesviridae family, are DNA viruses surrounded by an icosahedral capsid and have an envelope consisting of a lipid bilayer of cell origin and viral glycoproteins. Both are latent viruses responsible for infections that can reactivate over the years and is among the most well-established environmental risk factors in MS (Fierz, 2017).

EBV, the first virus isolated in a human tumor was identified by Epstein's group in a cell line derived from Burkitt lymphoma at 1964 (EPSTEIN et al., 1964). It is a ubiquitous herpesvirus, it is infection usually occurs in childhood and is asymptomatic in most of cases, latently persisting in the host throughout life, being detectable in peripheral blood B cells. EBV is the etiologic agent of infectious mononucleosis (IM) and has been associated with several neoplasms, including Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, and T-cell lymphoma (Amon and Farrell, 2005). Recently, EBV has been linked to an increased risk of MS. It has been described that individuals with a history of infectious mononucleosis may have two to three times greater risk of developing MS (Pender, 2011), higher prevalence of EBV in patients with MS (Wagner et al., 2004; Bjornevik et al., 2022), an age-dependent relationship between EBV infection and MS development (Bar-Or et al., 2020; Levin et al., 005), an increased immune response to EBV in patients with MS (Cepok et al., 005).

HHV-6 was first isolated in 1986 by Salahuddin and colleagues from peripheral blood mononuclear cells from adults with lymphoproliferative disorders (Salahuddin et al., 1986). HHV-6 is a β-herpesvirus and consists of 2 subtypes, HHV-6A and HHV-6B (Braun et al., 1997a). The seroprevalence is 95% worldwide (Campadelli-Fiume et al., 2023). Primary infection usually occurs during the first 2 years of life. While HHV-6B can cause Exanthem Subitum (Yamanishi et al., 1988), primary HHV-6A infection is often asymptomatic. The most common transmission route is horizontal, through saliva, since the salivary glands act as a valuable reservoir for this virus (Braun et al., 1997b). HHV-6 genomes can be found in many cells of healthy adults, including the CNS (Blumberg et al., 2000; Challoner et al., 1995), as it is highly neurotropic (Braun et al., 1997b) and neuroinvasive (Knox and Carrigan, 1995; Mackenzie et al., 1995). This virus has been documented in several cases of encephalitis (Carrigan et al., 1996; Cole et al., 1998; Paterson et al., 1999) and myelopathies (Knox and Carrigan, 1995; Mackenzie et al., 1995), including MS (Challoner et al., 1995).

In last years, published studies report the interaction of these viruses as a pathogenic mechanism in MS (Pender, 2011). A notable feature of many herpesviruses is the ability to cross the blood-brain barrier and reach the CNS (Salinas et al., 2010). Therefore, this study was carried out to investigate the presence of EBV/HHV-6 in patients with RRMS/SPMS and PPMS in patients from Rio de Janeiro City. Contributing to updating sociodemographic and clinical data from previous studies present in the literature.