Productive replication of Vif-chimeric HIV-1 in feline cells.
Nonprimate animal models of HIV-1 infection are prevented by missing cellular cofactors and by antiviral actions of species-specific host defense factors. These blocks are profound in rodents but may be less abundant in certain Carnivora. Here, we enabled productive, spreading replication and passage of HIV-1 in feline cells. Feline fibroblasts, T-cell lines, and primary peripheral blood mononuclear cells supported early and late HIV-1 life cycle phases in a manner equivalent to that of human cells, except that produced virions had low infectivity. Stable expression of feline immunodeficiency virus (FIV) Vif-green fluorescent protein (GFP) in HIV-1 entry receptor-complemented feline (CrFK) cells enabled robust spreading HIV-1 replication. FIV Vif colocalized with feline APOBEC3 (fA3) proteins, targeted them for degradation, and prevented G-->A hypermutation of the HIV-1 cDNA by fA3CH and fA3H. HIV-1 Vif was inactive against fA3s as expected and even paradoxically augmented restriction in some assays. In an interesting contrast, simian immunodeficiency virus SIVmac Vif had substantial anti-fA3 activities, which were complete against fA3CH and partial against fA3H. Moreover, both primate lentiviral Vifs colocalized with fA3s and could be pulled down from cell lysates by fA3CH. HIV-1 molecular clones that encode FIV Vif or SIVmac Vif (HIV-1(VF) and HIV-1(VS)) were then constructed. These viruses replicated productively in HIV-1 receptor-expressing CrFK cells and could be passaged serially to uninfected cells. Thus, with the exception of entry receptors, the cat genome can supply the dependency factors needed by HIV-1, and a main restriction can be countered by vif chimerism. The results raise the possibility that the domestic cat could yield an animal model of HIV-1 infection.
Stern
Melissa A
MA
Guggenheim 1811A, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Hu
Chunling
C
Saenz
Dyana T
DT
Fadel
Hind J
HJ
Sims
Olivia
O
Peretz
Mary
M
Poeschla
Eric M
EM
D000818:Animals; D002415:Cats; D002460:Cell Line; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D016346:Gene Products, vif / Q000235:genetics / Q000378:metabolism*; D016341:Genes, vif; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000821:virology; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000821:virology; D053586:Virus Internalization; D014779:Virus Replication / Q000502:physiology*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D016346:Gene Products, vif; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D043525:Cytosine Deaminase
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