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Multiple restrictions of human immunodeficiency virus type 1 in feline cells
Carsten Münk1, Jörg Zielonka, Hannelore Constabel
1Division of Medical Biotechnology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany. mueca@pei.de
Insights
Cats are not suitable animal models for HIV-1 research due to multiple cellular restrictions. Feline cells restrict human immunodeficiency virus type 1 (HIV-1) replication, primarily through APOBEC3 proteins inhibiting viral infectivity.
Area of Science:
- Virology
- Immunology
- Comparative Medicine
Background:
- Human immunodeficiency virus type 1 (HIV-1) replication is limited to human and chimpanzee cells, hindering the development of animal models for research.
- The absence of suitable animal models necessitates exploring alternative species for HIV-1 studies.
Purpose of the Study:
- To evaluate the susceptibility of feline (cat) cells to HIV-1 replication.
- To identify potential restrictions in feline cells that impede HIV-1 replication, pathogenesis, and therapeutic studies.
Main Methods:
- Assessed HIV-1 entry and replication in various feline cell lines (MYA-1, FeT-1C, CrFK, KE-R).
- Utilized pseudotyped vectors and HIV-1 luciferase reporter assays to measure viral activity.
- Investigated viral particle release and infectivity in feline cells.
- Identified and characterized feline apolipoprotein B-editing catalytic polypeptide 3 (feAPOBEC3) proteins' role in inhibiting HIV-1.
Main Results:
- Feline CD4 receptors blocked HIV-1 infection.
- Post-entry restrictions were observed in feline T-cell lines, leading to low viral reporter activity and Gag-Pol expression.
- Feline fibroblastic cells supported viral entry and gene expression but not spreading infection.
- A significant block in HIV-1 particle release occurred in KE-R cells.
- CrFK cells produced infectious particles, but their infectivity was reduced by feline APOBEC3H and APOBEC3CH through G-to-A hypermutations.
Conclusions:
- Feline cells exhibit multiple restrictions against HIV-1 replication, including entry barriers and post-entry blocks.
- Feline APOBEC3H and APOBEC3CH proteins are key factors inhibiting HIV-1 infectivity in feline cells.
- Cats are not suitable animal models for HIV-1 research due to these intrinsic cellular restrictions.
Abstract:
The productive replication of human immunodeficiency virus type 1 (HIV-1) occurs exclusively in defined cells of human or chimpanzee origin, explaining why heterologous animal models for HIV replication, pathogenesis, vaccination, and therapy are not available. This lack of an animal model for HIV-1 studies prompted us to examine the susceptibility of feline cells in order to evaluate the cat (Felis catus) as an animal model for studying HIV-1. Here, we report that feline cell lines harbor multiple restrictions with respect to HIV-1 replication. The feline CD4 receptor does not permit virus infection. Feline T-cell lines MYA-1 and FeT-1C showed postentry restrictions resulting in low HIV-1 luciferase reporter activity and low expression of viral Gag-Pol proteins when pseudotyped vectors were used. Feline fibroblastic CrFK and KE-R cells, expressing human CD4 and CCR5, were very permissive for viral entry and HIV-long terminal repeat-driven expression but failed to support spreading infection. KE-R cells displayed a profound block with respect to release of HIV-1 particles. In contrast, CrFK cells allowed very efficient particle production; however, the CrFK cell-derived HIV-1 particles had low specific infectivity. We subsequently identified feline apolipoprotein B-editing catalytic polypeptide 3 (feAPOBEC3) proteins as active inhibitors of HIV-1 particle infectivity. CrFK cells express at least three different APOBEC3s: APOBEC3C, APOBEC3H, and APOBEC3CH. While the feAPOBEC3C did not significantly inhibit HIV-1, the feAPOBEC3H and feAPOBEC3CH induced G to A hypermutations of the viral cDNA and reduced the infectivity approximately 10- to approximately 40-fold.
