The presence and the replicative state of human herpesvirus 6 (HHV-6) were evaluated in clinical samples from multiple sclerosis (MS) patients at the first time of MS diagnosis. HHV-6 variant B was present in peripheral blood mononuclear cells of 5/32 (15%) patients, but persisted with a latent infection. Viral sequences were present also in cerebrospinal fluid (CSF), both free in the liquid (7/32, 22%) and latent in the cellular fraction (3/32, 9%), as shown by analysis of viral transcription. In these cases, variant A was detected. HHV-6 DNA sequences present in the CSF were associated to mature viral particles. In fact, in vitro infectious assays of CSF showed the presence of replication-competent virions. These results show that about 20% of MS patients have active foci of HHV-6 variant A infection in the early stages of the disease and suggest that viral replication takes place within the central nervous system.
Perron H , Garson JA , Bedin F , Beseme F , Paranhos-Baccala G , Komurian-Pradel Fet al.Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis . Proc Natl Acad Sci USA1997; 94: 7583-7588 .
3.
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 .
Rotola A , Ravaioli T , Gonelli A , Dewhurst S , Cassai E , Di Luca D.U94 of human herpesvirus 6 is expressed in latently infected peripheral blood mononuclear cells and blocks viral gene expression in transformed lymphocytes in culture . Proc Natl Acad Sci USA1998; 95: 13911-13916 .
6.
Di Luca D , Mirandola P , Ravaioli T , Dolcetti R , Frigatti A , Bovenzi Pet al.Human herpesviruses 6 and 7 in salivary glands and shedding in saliva of healthy and human immunodeficiency virus positive individuals . J Med Virol1995; 45: 462-468 .
7.
Dockrell DH.Human herpesvirus 6: molecular biology and clinical features . J Med Microbiol2003; 52: 5-18 .
8.
Caselli E , Boni M , Bracci A , Rotola A , Cermelli C , Castellazzi Met al.Detection of antibodies directed against human herpesvirus 6 U94/REP in sera of patients affected by multiple sclerosis . J Clin Microbiol2002; 40: 4131-4137 .
9.
Cuomo L , Trivedi P , Cardillo MR , Gagliardi FM , Vecchione A , Caruso Ret al.Human herpesvirus 6 infection in neoplastic and normal brain tissue . J Med Virol2001; 63: 45-51 .
10.
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 .
11.
Kimberlin DW , Whitley RJ.Human herpesvirus-6: neurologic implications of a newly-described viral pathogen . J Neurovirol1998; 4: 474-485 .
12.
Yoshikawa T , Asano Y.Central nervous system complications in human herpesvirus-6 infection . Brain Dev2000; 22: 307-314 .
13.
Suga S , Yoshikawa T , Asano Y , Kozawa T , Nakashima T , Kobayashi Iet al.Clinical and virological analyses of 21 infants with exanthem subitum (roseola infantum) and central nervous system complications . Ann Neurol1993; 33: 597-603 .
14.
Drobyski WR , Knox KK , Majewski D , Carrigan DR.Brief report: fatal encephalitis due to variant B human herpes-virus-6 infection in a bone marrow-transplant recipient . N Engl J Med1994; 330: 1356-1360 .
15.
McCullers JA , Lakeman FD , Whitley RJ.Human herpesvirus 6 is associated with focal encephalitis . Clin Infect Dis1995; 21: 571-576 .
16.
Novoa LJ , Nagra RM , Nakawatase T , Edwards-Lee T , Tourtel-lotte WW , Cornford ME.Fulminant demyelinating encephalomyelitis associated with productive HHV-6 infection in an immunocompetent adult . J Med Virol1997; 52: 301-308 .
17.
Kamei A , Ichinohe S , Onuma R , Hiraga S , Fujiwara T.Acute disseminated demyelination due to primary human herpes-virus-6 infection . Eur J Pediatr1997; 156: 709-712 .
18.
Mackenzie IR , Carrigan DR , Wiley CA.Chronic myelopathy associated with human herpesvirus-6 . Neurology1995; 45: 2015-2017 .
19.
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 .
20.
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 .
21.
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 .
22.
Enbom M , Wang FZ , Fredrikson S , Martin C , Dahl H , Linde A.Similar humoral and cellular immunological reactivities to human herpesvirus 6 in patients with multiple sclerosis and controls . Clin Diagn Lab Immunol1999; 6: 545-549 .
23.
Chapenko S , Millers A , Nora Z , Logina I , Kukaine R , Murovska M.Correlation between HHV-6 reactivation and multiple sclerosis disease activity . J Med Virol2003; 69: 111-117 .
24.
Rotola A , Cassai E , Tola MR , Granieri E , Di Luca D.Human herpesvirus 6 is latent in peripheral blood of patients with relapsing-remitting multiple sclerosis . J Neurol Neurosurg Psychiatry1999; 67: 529-531 .
25.
Poser CM , Paty DW , Scheinberg L , McDonald WI , Davis FA , Ebers Johnson KPet al.New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol1983; 13: 227-231 .
26.
Walther W , Stein U , Eder C.RNA analysis using miniprep RNA in reverse transcription PCR . Biotechniques1994; 17: 674-675 .
27.
Di Luca D , Dolcetti R , Mirandola P , De Re V , Secchiero P , Carbone Aet al.Human herpesvirus 6: a survey of presence and variant distribution in normal peripheral lymphocytes and lymphoproliferative disorders . J Infect Dis1994; 170: 211-215 .
28.
Mirandola P , Menegazzi P , Merighi S , Ravaioli T , Cassai E , Di Luca D.Temporal mapping of transcripts in herpesvirus 6 variants . J Virol1998; 72: 3837-3844 .
29.
Rotola A , Caselli E , Cassai E , Tola MR , Granirei E , Di Luca D.Novel human herpesviruses and multiple sclerosis . J Neurovirol2000; 2: S88-S91 .
30.
Kim JS , Lee KS , Park JH , Kim MY , Shin WS.Detection of human herpesvirus 6 variant A in peripheral blood mono-nuclear cells from multiple sclerosis patients . Eur Neurol2000; 43: 170-173 .
31.
Alvarez-Lafuente R , Martin-Estefania C , de Las Heras V , Castrillo C , Picazo JJ , Varela de Seijas Eet al.Active human herpesvirus 6 infection in patients with multiple sclerosis . Arch Neurol2002; 59: 929-933 .
32.
Di Luca D , Mirandola P , Ravaioli T , Bigoni B , Cassai E.Distribution of HHV-6 variants in human tissues . Infect Agents Dis1996; 5: 203-214 .
33.
Hall CB , Caserta MT , Schnabel KC , Long C , Epstein LG , Insel RAet al.Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A . Clin Infect Dis1998; 26: 132-137 .
34.
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 .
35.
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 .
36.
Ablashi DV , Eastman HB , Owen CB , Roman MM , Friedman J , Zabriskie JBet al.Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients . J Clin Virol2000; 16: 179-191 .
37.
Albright AV , Lavi E , Black JB , Goldberg S , O’Connor MJ , Gonzales-Scarano F.The effect of human herpesvirus-6 (HHV-6) on cultured human neural cells: oligodendrocytes and microglia . J Neurovirol1998; 4: 486-494 .
38.
Flamand L , Gosselin J , D’Addario M , Hiscott J , Ablashi DV , Gallo RCet al.Human herpesvirus 6 induces interleukin-1 beta and tumor necrosis factor alpha, but not interleukin-6, in peripheral blood mononuclear cell cultures . J Virol1991; 65: 5105-5110 .
39.
Gosselin J , Flamand L , D’Addario M , Hiscott J , Stefanescu I , Ablashi DVet al.Modulatory effects of Epstein-Barr, herpes simplex, and human herpes-6 viral infections and coinfections on cytokine synthesis. A comparative study . J Immunol1992; 149: 181-187 .
40.
Perron H , Perin JP , Rieger F , Alliel PM.Particle-associated retroviral RNA and tandem RGH/HERV-W copies on human chromosome 7q: possible components of a ‘chain-reaction’ triggered by infectious agents in multiple sclerosis?J Neurovirol2000; 2: S67-S75 .
