The function and evolution of the restriction factor Viperin in primates was not driven by lentiviruses.
BACKGROUND
Viperin, also known as RSAD2, is an interferon-inducible protein that potently restricts a broad range of different viruses such as influenza, hepatitis C virus, human cytomegalovirus and West Nile virus. Viperin is thought to affect virus budding by modification of the lipid environment within the cell. Since HIV-1 and other retroviruses depend on lipid domains of the host cell for budding and infectivity, we investigated the possibility that Viperin also restricts human immunodeficiency virus and other retroviruses.


RESULTS
Like other host restriction factors that have a broad antiviral range, we find that viperin has also been evolving under positive selection in primates. The pattern of positive selection is indicative of Viperin's escape from multiple viral antagonists over the course of primate evolution. Furthermore, we find that Viperin is interferon-induced in HIV primary target cells. We show that exogenous expression of Viperin restricts the LAI strain of HIV-1 at the stage of virus release from the cell. Nonetheless, the effect of Viperin restriction is highly strain-specific and does not affect most HIV-1 strains or other retroviruses tested. Moreover, knockdown of endogenous Viperin in a lymphocytic cell line did not significantly affect the spreading infection of HIV-1.


CONCLUSIONS
Despite positive selection having acted on Viperin throughout primate evolution, our findings indicate that Viperin is not a major restriction factor against HIV-1 and other retroviruses. Therefore, other viral lineages are likely responsible for the evolutionary signatures of positive selection in viperin among primates.
Department of Microbiology, Fred Hutchinson Cancer Research Center,University of Washington, Seattle, WA 98109-1024, USA.
Efrem S
ES
Lim
Lily I
LI
Wu
Harmit S
HS
Malik
Michael
M
Emerman
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D019143:Evolution, Molecular; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D008969:Molecular Sequence Data; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010802:Phylogeny; D011323:Primates; D011506:Proteins / Q000145:classification / Q000378:metabolism*; D012641:Selection, Genetic; D014162:Transfection; D020298:U937 Cells; D053586:Virus Internalization; D057074:Virus Release; D000090123:Viperin Protein
D016899:Interferon-beta; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; C444427:RSAD2 protein, human; D000090123:Viperin Protein