Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus env sequences.
BACKGROUND
Multiple sclerosis-associated retrovirus (MSRV) RNA sequences have been detected in patients with multiple sclerosis (MS) and are related to the multi-copy human endogenous retrovirus family type W (HERV-W). Only one HERV-W locus (ERVWE1) codes for a complete HERV-W Env protein (Syncytin-1). Syncytin-1 and the putative MSRV Env protein have been involved in the pathogenesis of MS. The origin of MSRV and its precise relation to HERV-W were hitherto unknown.


RESULTS
By mapping HERV-W env cDNA sequences (n = 332) from peripheral blood mononuclear cells of patients with MS and healthy controls onto individual genomic HERV-W env elements, we identified seven transcribed HERV-W env loci in these cells, including ERVWE1. Transcriptional activity of individual HERV-W env elements did not significantly differ between patients with MS and controls. Remarkably, almost 30% of HERV-W env cDNAs were recombined sequences that most likely arose in vitro between transcripts from different HERV-W env elements. Re-analysis of published MSRV env sequences revealed that all of them can be explained as originating from genomic HERV-W env loci or recombinations among them. In particular, a MSRV env clone previously used for the generation of monoclonal antibody 6A2B2, detecting an antigen in MS brain lesions, appears to be derived from a HERV-W env locus on chromosome Xq22.3. This locus harbors a long open reading frame for an N-terminally truncated HERV-W Env protein.


CONCLUSIONS
Our data clarify the origin of MSRV env sequences, have important implications for the status of MSRV, and open the possibility that a protein encoded by a HERV-W env element on chromosome Xq22.3 may be expressed in MS brain lesions.
Institute of Virology, Saarland University Hospital, Homburg, Germany. G_1982@web.de
Georg
G
Laufer
Jens
J
Mayer
Benedikt F
BF
Mueller
Nikolaus
N
Mueller-Lantzsch
Klemens
K
Ruprecht
D000328:Adult; D001483:Base Sequence; D003001:Cloning, Molecular; D018076:DNA, Complementary; D020077:Endogenous Retroviruses / Q000235:genetics / Q000378:metabolism; D005260:Female; D015686:Gene Products, env / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D009103:Multiple Sclerosis / Q000821:virology*; D011995:Recombination, Genetic; D016415:Sequence Alignment; D014158:Transcription, Genetic
D018076:DNA, Complementary; D015686:Gene Products, env