SUMMARYA group of 20 Icelandic sheep were infected intracerebrally with visna virus strain 1514, and 209 virus isolates were obtained from the blood, cerebrospinal fluid, and central nervous system (CNS) over a period of 7 years, during which eight animals developed clinical signs of visna necessitating sacrifice. (i) Using type-specific antisera, it was found that 12 (16%) of 76 isolates tested escaped neutralization. These 12 variant viruses were distributed randomly among animals and over time, and did not replace the infecting strain even though all sheep developed homotypic antibody within 3 months of infection. The one exception was sheep no. 1557 (an animal without clinical visna), where the last six isolates were variants. (ii) A total of 35 blood and CNS isolates from seven of these sheep (including five with clinical visna) were tested against serial samples of their own sera. Autologous antisera neutralized all isolates tested with the exception of isolates from sheep 1557. None of the isolates obtained at sacrifice from the five sheep with clinical visna escaped neutralization with autologous antisera. These data suggest that although variant viruses are encountered at considerable frequency during long-term infection of Icelandic sheep, the variants usually do not replace the infecting strain. Antigenic drift does not appear to be essential for virus persistence or for the development of clinically evident CNS lesions.

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In order to analyse the pattern of sequence variation in maedi-visna virus (MVV) in persistently infected sheep and to answer the question of whether antigenic variants are selected in a long-term MVV infection, an 87 bp variable region in the env gene of ten antigenic variants and 24 nonvariants was sequenced. Nine of the ten antigenic variants had mutations in this region, comprising 24 point mutations and a deletion of 3 bp. Twenty-three of the point mutations (96 %) were nonsynonymous. There was only a single mutation in this region in the 24 non-variants. A type-specific neutralizing antibody response appeared in all the sheep 2-5 months post-infection, and in most sheep more broadly reacting neutralizing antibodies appeared up to 4 years later. All the antigenic variants were neutralized by the broadly reacting sera. It is noteworthy that the antigenic variants were isolated at a time when only the type-specific antibodies were acting, before the broadly reacting antibodies appeared. The same picture emerged when molecularly cloned virus was used for infection. Three sheep were infected with a molecularly cloned virus, and of six virus isolates, one was an antigenic variant. This variant arose in the absence of broadly reacting antibodies. The results indicate that there is selection for mutants that escape neutralization. IntroductionMaedi-visna virus (MVV) establishes a lifelong infection of sheep, leading either to progressive meningoencephalomyelitis, characterized by weakness or paralysis of the hind legs (visna) or lung lesions of progressive pneumonia (maedi) (Sigurdsson & Pa! lsson, 1958). MVV is a member of the Lentivirus subfamily of retroviruses, and its primary target cells are considered to be of the monocyte lineage (Gendelman et al., 1986). MVV elicits an immune response in the host, both humoral and cell-mediated (Griffin et al., 1978 ;Larsen et al., 1982 ;Sihvonen, 1981 ;Thormar & Helgado! ttir, 1965 ;Torsteinsdo! ttir et al., 1992), and the persistence of the virus in the face of a strong immune response has long been a puzzle. It has been proposed that one way for the virus to escape the Author for correspondence : Valgerdur Andre! sdo! ttir.Fax j354 5673979. e-mail valand!hi.is †Present address : deCode Genetics, Reykjavı! k, Iceland. ‡Present address : Sigma-Aldrich Fine Chemicals, St Louis, MO 63103, USA.The sequences of the env gene of the three antigenic variants have been submitted to GenBank, accession numbers immune response is by continuous change of epitopes through mutation (Gudnado! ttir, 1974). Antigenic variation has indeed been documented for all lentiviruses (Burns et al., 1993 ;Ellis et al., 1987 ;Gudnado! ttir, 1974 ;Kono et al., 1973 ;McGuire et al., 1988 ;McKeating et al., 1989 ;Montelaro et al., 1984 ;Narayan et al., 1977 ;Siebelink et al., 1993 ;Wolfs et al., 1991), but its significance for pathogenicity has been disputed (Cheevers et al., 1999 ;Lutley et al., 1983 ;Thormar et al., 1983 ;Wolinsky et al., 1996). The envelope genes of the lentiviruses are divided int...