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.

Lineage-Specific Viral Hijacking of Non-canonical E3 Ubiquitin Ligase Cofactors in the Evolution of Vif Anti-APOBEC3 Activity

“…Intriguingly, a pair of mutants in MVV Vif and Capsid (P205S and L120R, respectively) results in a restricted growth phenotype, while neither mutant alone impacts replication (Gudmundsson et al, 2005). Whether or not this is related to the MVV Vif interaction with CYPA is under investigation.…”

Low proviral small ruminant lentivirus load as biomarker of natural restriction in goats

“…Thus, in vitro infection confirmed ex vivo findings being replication highly inhibited in the LPL animal. Interestingly, differences were smaller when infecting with CAEV-Co strain that encodes slightly divergent CA and Env proteins (Gudmundsson et al, 2005;Haflidadottir et al, 2008), likely escaping from the restriction exerted by SF1000L. Primate lentiviruses in which punctual mutations have been introduced in host-interacting proteins such as Gag or Env, have demonstrated escape from the specific binding of restriction factors with specific viral determinants (Veillette et al, 2013).…”

Small Ruminant Lentiviruses and Human Immunodeficiency Virus: Cousins that Take a Long View

“…interaction with and so inhibition of APOBEC3 proteins (cytidine deaminases). In vivo a single amino acid mutation in VIF linked to another amino acid mutation in the CA protein changes a neurovirulent molecular clone of VMV to an apathogenic clone [156] showing how important this function can be for the virus.…”