Duplicated Sequence Motif in the Long Terminal Repeat of Maedi-Visna Virus Extends Cell Tropism and Is Associated with Neurovirulence

Abstract

Maedi-visna virus (MVV) is a lentivirus of sheep causing chronic inflammatory disease of the lungs (maedi)and the nervous system (visna). We have previously shown that a duplicated sequence in the long terminal repeat (LTR) of MVV is a determinant of cell tropism. Here, we demonstrate that deletion of a CAAAT sequence from either one of the repeats resulted in poor virus growth in sheep choroid plexus cells. A duplication in the LTR encompassing the CAAAT sequence was found in four neurological field cases that were sequenced, but no duplication was present in the LTRs from seven maedi cases; one maedi isolate was mixed. These results indicate that the duplication in the LTR is associated with neurovirulence.

Genome Analysis of Small-Ruminant Lentivirus Genotype E: a Caprine Lentivirus with Natural Deletions of the dUTPase Subunit, vpr -Like Accessory Gene, and 70-Base-Pair Repeat of the U3 Region

“…The low-pathogenicity SRLVs characterized so far have shown that deletions or mutations in the long terminal repeat (LTR) may be associated with variations in virulence, likely due to the presence of replication enhancer elements such as AP1, AML, tumor necrosis factor-␣, and gamma interferon response elements (1,11). Additional information about virulence factors has been produced in in vitro and in vivo studies by using genetic manipulation of infectious molecular clones (7,8,10,19,23).…”

“…Therefore, it is important to establish the role of bone marrow as a virus reservoir in genotype E infection, which is still controversial in dUTPase-positive strains (6,14). In addition, in all previous studies in which dUTPase, vpr-like, and U3 70-bp repeat sequences were independently deleted from the CAEV genome, a reduction in viral load and/or disease progression was recorded, thus providing indirect evidence that genotype E exhibits a low-pathogenicity potential in vivo (9,11,20).…”

Development and comparison of strain specific gag and pol real-time PCR assays for the detection of Visna/maedi virus

“…Since then, several other members of this genus of the family Retroviridae have been identified, including caprine arthritis encephalitis virus (CAEV), equine infectious anemia virus (EIAV) and human, simian, feline and bovine immunodeficiency viruses (HIV, SIV, FIV and BIV respectively). VMV has long been considered the prototype lentivirus ( Carey andDalziel, 1993 andClements, 1989) and has been widely employed to study many aspects of lentiviral infections, such as the molecular mechanisms underlying viral tropism ( Agnarsdóttir et al, 2000, Barros et al, 2005, Chebloune et al, 1996and Óskarsson et al, 2007, persistence and pathogenesis ( Torsteinsdottir et al, 2007), routes of viral transmission ( Blacklaws et al, 2004) and strategies to eradicate or prevent the infection ). The British VMV strain EV1 was isolated from a sheep displaying symptoms of arthritis and pneumonia and its complete genome was cloned and sequenced ( Sargan et al, 1991).…”

LTR promoter activity of SRLV genotype E, strain Roccaverano

“…LTRs have been described as viral transcription promoters and their U3 region as an enhancer where transcription factorbinding sites are present. Several studies have investigated the relative role of each individual site in enhancing replication and tropism (Oskarsson et al 2007;Murphy et al 2007). Several SRLV strains characterized so far contain repeats within U3 that increase downstream transcription and increased virulence.…”

“…Several SRLV strains characterized so far contain repeats within U3 that increase downstream transcription and increased virulence. Actually, it has been demonstrated that deletion of a CAAAT sequence from either one of the repeats results in poor virus growth in sheep choroid plexus cells, suggesting that U3 duplication is associated with neurovirulence (Oskarsson et al 2007). On the other hand, MVV-AML-defective chimeric viruses showed both lower replication and promoter activity due to the absence of the U3 repeat.…”