Simultaneous Mutations in CA and Vif of Maedi-Visna Virus Cause Attenuated Replication in Macrophages and Reduced Infectivity In Vivo

ABSTRACT Maedi-visna virus (MVV) is a lentivirus of sheep sharing several key features with the primate lentiviruses. The virus causes slowly progressive diseases, mainly in the lungs and the central nervous system of sheep. Here, we investigate the molecular basis for the differential growth phenotypes of two MVV isolates. One of the isolates, KV1772, replicates well in a number of cell lines and is highly pathogenic in sheep. The second isolate, KS1, no longer grows on macrophages or causes disease. The two virus isolates differ by 129 nucleotide substitutions and two deletions of 3 and 15 nucleotides in the env gene. To determine the molecular nature of the lesions responsible for the restrictive growth phenotype, chimeric viruses were constructed and used to map the phenotype. An L120R mutation in the CA domain, together with a P205S mutation in Vif (but neither alone), could fully convert KV1772 to the restrictive growth phenotype. These results suggest a functional interaction between CA and Vif in MVV replication, a property that may relate to the innate antiretroviral defense mechanisms in sheep.

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Maedi-visna virus Vif protein uses motifs distinct from HIV-1 Vif to bind zinc and cofactor required for A3 degradation

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015828 ◽

2020 ◽

pp. jbc.RA120.015828

Author(s):

Kirsten M. Knecht ◽

Yingxia Hu ◽

Diana Rubene ◽

Matthew Cook ◽

Samantha J Ziegler ◽

...

Keyword(s):

Viral Infections ◽

Zinc Ion ◽

Binding Motif ◽

Cytidine Deaminases ◽

Visna Virus ◽

Primate Lentiviruses ◽

Maedi Visna Virus ◽

Hiv 1

The mammalian apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) family of cytidine deaminases restrict viral infections by mutating viral DNA and impeding reverse transcription. To overcome this antiviral activity, most lentiviruses express a viral accessory protein called Vif, which recruits A3 proteins to Cullin-RING E3 ubiquitin ligases such as Cul5 for ubiquitylation and subsequent proteasomal degradation. While Vif proteins from primate lentiviruses like HIV-1 utilize the transcription factor CBFβ as a non-canonical cofactor to stabilize the complex, maedi-visna virus (MVV) Vif hijacks cyclophilin A (CypA) instead. Since CBFβ and CypA are both highly conserved among mammals, the requirement for two different cellular cofactors suggests that these two A3-targeting Vif proteins have different biochemical and structural properties. To investigate this topic, we used a combination of in vitro biochemical assays and in vivo A3 degradation assays to study motifs required for MVV Vif to bind zinc ion, Cul5, and the cofactor CypA. Our results demonstrate that while some common motifs between HIV-1 Vif and MVV Vif are involved in recruiting Cul5, different determinants in MVV Vif are required for cofactor binding and stabilization of the E3 ligase complex, such as the zinc-binding motif and N- and C-terminal regions of the protein. Results from this study advance our understanding of the mechanism of MVV Vif recruitment of cellular factors and the evolution of lentiviral Vif proteins.

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In vivo depletion of CD8+ cells does not affect primary maedi visna virus infection in sheep

Veterinary Immunology and Immunopathology ◽

10.1016/s0165-2427(99)00061-6 ◽

1999 ◽

Vol 70 (3-4) ◽

pp. 173-187 ◽

Cited By ~ 5

Author(s):

Kristina Eriksson ◽

Elizabeth McInnes ◽

Susanna Ryan ◽

Paul Tonks ◽

Ian McConnell ◽

...

Keyword(s):

Virus Infection ◽

Cd8 Cells ◽

Visna Virus ◽

Maedi Visna Virus

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Demonstration of Coinfection with and Recombination by Caprine Arthritis-Encephalitis Virus and Maedi-Visna Virus in Naturally Infected Goats

Journal of Virology ◽

10.1128/jvi.00126-07 ◽

2007 ◽

Vol 81 (10) ◽

pp. 4948-4955 ◽

Cited By ~ 43

Author(s):

Giuliano Pisoni ◽

Giuseppe Bertoni ◽

Maria Puricelli ◽

Marina Maccalli ◽

Paolo Moroni

Keyword(s):

Mononuclear Cells ◽

Gene Segment ◽

Encephalitis Virus ◽

Nucleotide Sequencing ◽

Caprine Arthritis Encephalitis Virus ◽

Virus Group ◽

Visna Virus ◽

Maedi Visna Virus ◽

Different Strains

ABSTRACT Recombination of different strains and subtypes is a hallmark of lentivirus infections, particularly for human immunodeficiency virus, and contributes significantly to viral diversity and evolution both within individual hosts and within populations. Recombinant viruses are generated in individuals coinfected or superinfected with more than one lentiviral strain or subtype. This, however, has never been described in vivo for the prototype lentivirus maedi-visna virus of sheep and its closely related caprine counterpart, the caprine arthritis-encephalitis virus. Cross-species infections occur in animals living under natural conditions, which suggests that dual infections with small-ruminant lentiviruses (SRLVs) are possible. In this paper we describe the first documented case of coinfection and viral recombination in two naturally infected goats. DNA fragments encompassing a variable region of the envelope glycoprotein were obtained from these two animals by end-limiting dilution PCR of peripheral blood mononuclear cells or infected cocultures. Genetic analyses, including nucleotide sequencing and heteroduplex mobility assays, showed that these goats harbored two distinct populations of SRLVs. Phylogenetic analysis permitted us to assign these sequences to the maedi-visna virus group (SRLV group A) or the caprine arthritis-encephalitis virus group (SRLV group B). SimPlot analysis showed clear evidence of A/B recombination within the env gene segment of a virus detected in one of the two goats. This case provides conclusive evidence that coinfection by different strains of SRLVs of groups A and B can indeed occur and that these viruses actually recombine in vivo.

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CD8+ lymphocytes in bronchoalveolar lavage and blood: in vivo indicators of lung pathology caused by maedi-visna virus

Veterinary Immunology and Immunopathology ◽

10.1016/0165-2427(95)05460-n ◽

1995 ◽

Vol 49 (1-2) ◽

pp. 89-100 ◽

Cited By ~ 10

Author(s):

L. Luján ◽

I. Begara ◽

D.D.S. Collie ◽

N.J. Watt

Keyword(s):

Bronchoalveolar Lavage ◽

Lung Pathology ◽

Visna Virus ◽

Maedi Visna Virus

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Acute in vivo neurotoxicity of peptides from Maedi Visna virus transactivating protein Tat

Brain Research ◽

10.1016/s0006-8993(99)01407-9 ◽

1999 ◽

Vol 830 (2) ◽

pp. 285-291 ◽

Cited By ~ 11

Author(s):

Isabella Starling ◽

Ann Wright ◽

Gordon Arbuthnott ◽

Gordon Harkiss

Keyword(s):

Visna Virus ◽

Maedi Visna Virus

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The long terminal repeat is a determinant of cell tropism of maedi-visna virus

Journal of General Virology ◽

10.1099/0022-1317-81-8-1901 ◽

2000 ◽

Vol 81 (8) ◽

pp. 1901-1905 ◽

Cited By ~ 25

Author(s):

Gudrún Agnarsdóttir ◽

Holmfrídur Thorsteinsdóttir ◽

Thórdur óskarsson ◽

Sigrídur Matthíasdóttir ◽

Benedikta St. Haflidadóttir ◽

...

Keyword(s):

Long Terminal Repeat ◽

Pcr Amplification ◽

Cell Types ◽

Terminal Repeat ◽

Cell Tropism ◽

Visna Virus ◽

Pcr Products ◽

The Central Nervous System ◽

Maedi Visna Virus

Maedi-visna virus (MVV) is a lentivirus of sheep, mainly affecting the lungs and the central nervous system. Long terminal repeat (LTR) sequence variability is common in tissue culture-derived isolates of MVV as well as those of other lentiviruses. The role of this sequence variation in MVV replication has not been explored. PCR amplification of the LTRs of an MVV isolate revealed two product sizes, the larger containing a 53 bp duplication. PCR products containing the two size variants of the LTRs were cloned into an infectious molecular clone of MVV and the resulting chimeric viruses were tested for growth in various cell types. The chimeric virus containing only one copy of the 53 bp sequence was found to grow more slowly in sheep choroid plexus cells, sheep fibroblasts and sheep synovial cells than the virus with the 53 bp duplication. Both viruses grew equally well in macrophages. These results indicate that the LTRs determined the extended cell tropism of MVV.

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