Multiple sclerosis (MS) is thought to be precipitated by environmental factors, potentially including viruses, in genetically susceptible individuals and recently human herpesvirus 6 (HHV-6) has been associated with the disease. We have analysed post mortem brain for the presence, variant type and quantity of HHV-6 by PCR. A total of 124 samples from seven anatomically defined regions of brain were tested from MS cases and controls. HHV-6 DNA was detected in 41% and 44% of MS case and control samples. The median viral loads were 11 and 9 genome copies/mg DNA in cases and controls respectively and the viral load was not increased in lesions. Except in one instance, the HHV-6 DNA detected was variant B. There was no apparent difference in the distribution of HHV-6 DNA in the brains of MS cases versus controls, nor between normal appearing and lesional tissue in MS cases. Periventricular regions of the brain were more frequently positive for HHV-6 DNA in both MS cases and controls, although this difference was not statistically significant. These studies confirm the neurotropism of HHV-6 but do not demonstrate differences in the distribution, variant type or quantity of HHV-6 in brains from patients with MS versus controls.
Challoner PB , Smith KT , Parker JD , MacLeod DL , Coulter SN , Rose TMet al.Plaque-associated expression of human herpesvirus 6 in multiple sclerosis . Proc Natl Acad Sci USA1995; 92: 7440-7444 .
2.
Yamanishi K , Okuno T , Shiraki K , Takahashi M , Kondo T , Asano Yet al.Identification of human herpesvirus-6 as a causal agent for exanthem subitum . Lancet1988; 1: 1065-1067 .
3.
Clark DA , Griffiths PD.Human herpesvirus 6: relevance of infection in the immunocompromised host . Br J Haematol2003; 120: 384-395 .
4.
Ablashi D , Agut H , Berneman Z , Campadelli-Fiume G , Carrigan D , Ceccerini-Nelli Let al.Human herpesvirus-6 strain groups: a nomenclature . Arch Virol1993; 129: 363-366 .
5.
Knox KK , Brewer JH , Henry JM , Harrington DJ , Carrigan DR.Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease . Clin Infect Dis2000; 31: 894-903 .
6.
Coates AR , Bell J.HHV-6 and multiple sclerosis . Nat Med1998; 4: 537-538 .
7.
Friedman JE , Lyons MJ , Cu G , Ablashi DV , Whitman JE , Edgar Met al.The association of the human herpesvirus-6 and MS . Mult Scler1999; 5: 355-362 .
8.
Sanders VJ , Felisan S , Waddell A , Tourtellotte WW.Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction . J Neurovirol1996; 2: 249-258 .
9.
Soldan SS , Berti R , Salem N , Secchiero P , Flamand L , Calabresi PAet al.Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA . Nat Med1997; 3: 1394-1397 .
10.
Akhyani N , Berti R , Brennan MB , Soldan SS , Eaton JM , McFarland HFet al.Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased prevalence of HHV-6A in patients with multiple sclerosis . J Infect Dis2000; 182: 1321-1325 .
11.
Tomsone V , Logina I , Millers A , Chapenko S , Kozireva S , Murovska M.Association of human herpesvirus 6 and human herpesvirus 7 with demyelinating diseases of the nervous system . J Neurovirol2001; 7: 564-569 .
12.
Berti R , Brennan MB , Soldan SS , Ohayon JM , Casareto L , McFarland HFet al.Increased detection of serum HHV-6 DNA sequences during multiple sclerosis (MS) exacerbations and correlation with parameters of MS disease progression . J Neurovirol2002; 8: 250-256 .
13.
Tejada-Simon MV , Zang YC , Hong J , Rivera VM , Killian JM , Zhang JZ.Detection of viral DNA and immune responses to the human herpesvirus 6 101-kilodalton virion protein in patients with multiple sclerosis and in controls . J Virol2002; 76: 6147-6154 .
14.
Wilborn F , Schmidt CA , Brinkmann V , Jendroska K , Oettle H , Siegert W.A potential role for human herpesvirus type 6 in nervous system disease . J Neuroimmunol1994; 49: 213-214 .
15.
Martin C , Enbom M , Soderstrom M , Fredrikson S , Dahl H , Lycke Jet al.Absence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis . Acta Neurol Scand1997; 95: 280-283 .
16.
Fillet AM , Lozeron P , Agut H , Lyon-Caen O , Liblau R.HHV-6 and multiple sclerosis . Nat Med1998; 4: 537-537 .
17.
Goldberg SH , Albright AV , Lisak RP , Gonzalez-Scarano F.Polymerase chain reaction analysis of human herpesvirus-6 sequences in the sera and cerebrospinal fluid of patients with multiple sclerosis . J Neurovirol1999; 5: 134-139 .
18.
Mirandola P , Stefan A , Brambilla E , Campadelli-Fiume G , Grimaldi LM.Absence of human herpesvirus 6 and 7 from spinal fluid and serum of multiple sclerosis patients . Neurology1999; 53: 1367-1368 .
19.
Nielsen L , Larsen AM , Munk M , Vestergaard BF.Human herpesvirus-6 immunoglobulin G antibodies in patients with multiple sclerosis . Acta Neurol Scand1997; 169: 76-78 .
20.
Xu Y , Linde A , Fredrikson S , Dahl H , Winberg G.HHV-6 A-or B-specific P41 antigens do not reveal virus variant-specific IgG or IgM responses in human serum . J Med Virol2002; 66: 394-399 .
21.
Tejada-Simon MV , Zang YC , Hong J , Rivera VM , Zhang JZ.Cross-reactivity with myelin basic protein and human herpes-virus-6 in multiple sclerosis . Ann Neurol2003; 53: 189-197 .
22.
Kidd IM , Clark DA , Bremner JA , Pillay D , Griffiths PD , Emery VC.A multiplex PCR assay for the simultaneous detection of human herpesvirus 6 and human herpesvirus 7, with typing of HHV-6 by enzyme cleavage of PCR products . J Virol Methods1998; 70: 29-36 .
23.
Clark DA , Ait-Khaled M , Wheeler AC , Kidd IM , McLaughlin JE , Johnson MAet al.Quantification of human herpesvirus 6 in immunocompetent persons and post-mortem tissues from AIDS patients by PCR . J Gen Virol1996; 77: 2271-2275 .
24.
Kidd IM , Clark DA , Emery VC.A non-radioisotopic quantitative competitive polymerase chain reaction method: application in measurement of human herpesvirus 7 load . J Virol Methods2000; 87: 177-181 .
25.
Griffiths PD , Ait-Khaled M , Bearcroft CP , Clark DA , Quaglia A , Davies SEet al.Human herpesvirus 6 and 7 as potential pathogens after liver transplant: prospective comparison with the effect of cytomegalovirus . J Med Virol1999; 59: 496-501 .
26.
Kidd IM , Clark DA , Sabin CA , Andrew D , Hassan-Walker AF , Sweny Pet al.Prospective study of human betaherpesviruses after renal transplantation: association of human herpesvirus 7 and cytomegalovirus co-infection with cytomegalovirus disease and increased rejection . Transplantation2000; 69: 2400-2404 .
27.
Luppi M , Barozzi P , Maiorana A , Marasca R , Torelli G.Human herpesvirus 6 infection in normal human brain tissue . J Infect Dis1994; 169: 943-944 .
28.
Chan PK , Ng HK , Hui M , Cheng AF.Prevalence and distribution of human herpesvirus 6 variants A and B in adult human brain . J Med Virol2001; 64: 42-46 .
29.
Xu Y , Linde A , Dahl H , Winberg G.Definition of a divergent epitope that allows differential detection of early protein p41 from human herpesvirus 6 variants A and B . J Clin Microbiol2001; 39: 1449-1455 .
30.
Goodman AD , Mock DJ , Powers JM , Baker JV , Blumberg BM.Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions . J Infect Dis2003; 187: 1365-1376 .
31.
Cermelli C , Berti R , Soldan SS , Mayne M , D’ambrosia JM , Ludwin SKet al.High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser micro-dissection . J Infect Dis2003; 187: 1377-1387 .
