Herpesvirus active replication in multiple sclerosis A genetic control? Marta Garcia-Montojo a , Alfonso Martinez b , Virginia De Las Heras a , Maria Inmaculada Dominguez-Mozo a , Maria del Carmen Cenit b , Maria López-Cavanillas b , Angel Garcia-Martinez a , Ana Maria Arias-Leal a , Emilio Gomez de la Concha b , Elena Urcelay b , Rafael Arroyo a , Roberto Alvarez-Lafuente a, ⁎ a Servicio de Neurología, Hospital Clínico San Carlos, Madrid 28040, Spain b Servicio de Inmunología, Hospital Clínico San Carlos, Madrid 28040, Spain abstract article info Article history: Received 29 April 2011 Received in revised form 1 September 2011 Accepted 5 September 2011 Available online 1 October 2011 Keywords: HHV-6 MHC2TA CD46 Multiple sclerosis PCR Although the etiology of multiple sclerosis (MS) is unknown, it is generally believed that genetic, immuno- logic, and environmental factors are involved. The objectives of this study were: 1. to analyze if a genetic con- trol could explain why HHV-6 would be able to actively replicate in a subset of MS patients but not in controls; 2. to study if MS patients with HHV-6 active replication are clinically different from those without HHV-6 active replication. A total of 195 MS patients and 195 controls were analyzed for two SNPs at the MHC2TA locus and two SNPs at the CD46 locus. Furthermore, the MS cohort was analyzed by PCR for the detection of HHV-6 genomes in five serum samples collected every six months along two-year follow-up. We found that 59/195 (30.2%) MS patients had at least one HHV-6 positive serum sample. No statistical sig- nificant difference was found for the two genes when the comparison was made between MS patients and controls; however, a statistical significance was found for the two polymorphisms of MHC2TA when we com- pared MS patients with active replication and controls (p = 0.0000004 for rs4774C and p = 0.011 for rs3087456G). Furthermore, increased significant differences were found for MHC2TA and CD46 when we compared interferon beta responders and non-responders within MS patients. In conclusion, we describe a gene–environment interaction in MS patients between HHV-6 and MHC2TA and CD46 that should be further studied to clarify if that interaction could be a genetic control. The results show that MS patients without HHV-6 active replication are better responders to interferon beta treatment than those with HHV-6 active replication. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system. The pathogenesis of MS is not well understood; however, there are strong evidences for an autoimmune component. Although the etiology of MS is unknown, it is generally believed that genetic, immunologic, and environmental factors are involved. Viruses have been long associated with MS, and among them, human herpesviruses like human herpesvirus 6 (HHV-6) have been deeply studied in the last years. The HHV-6 is a lymphotropic virus closely related to human cytomegalovirus (CMV) and human herpesvirus-human 7 (HHV-7). It has a worldwide distribution and a high prevalence in the general adult population [1]. Many recent publications that have been published on MS and viruses analyze the active replication rate of HHV-6 in MS patients versus controls through the analysis of the presence of HHV-6 genomes in serum samples [2–24]. As we can see in Table 1, while the mean DNA prevalence of HHV-6 in MS patients is more than seventeen per cent, controls only reach one point eight; then, the active replication of HHV-6 in MS patients increased tenfold. If we take together all these results, we would obtain a high statistically significant differ- ence (p = 0.000001, odds ratio = 11.7). Then, is there a genetic con- trol that could explain that a high prevalent virus in the worldwide population is able to actively replicate in a subset of MS patients but not in controls? Are these MS patients with HHV-6 active replication clinically different from those without HHV-6 active replication? To study these questions we analyzed in a MS cohort: two polymor- phisms of MHC2TA, a gene that has been previously associated with MS, [25] and also with HHV-6 [20], two polymorphisms of CD46, the gene that codes for the cellular receptor of HHV-6, [26] and the HHV-6 replicative status through the analysis of HHV-6 genomes in serum samples by quantitative real-time PCR along two-year follow-up. Journal of the Neurological Sciences 311 (2011) 98–102 ⁎ Corresponding author at: Neurology Service, Hospital Clínico San Carlos, C./Profesor Martín Lagos s/n. 28040 Madrid, Spain. Tel.: +34 91 3303000x7440; fax: +34 91 3303457. E-mail address: ralvarezlafuente@yahoo.es (R. Alvarez-Lafuente). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.09.001 Contents lists available at SciVerse ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns