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Retrovirology. 2018 May 16;15(1):38. doi: 10.1186/s12977-018-0419-0.

Replacement of feline foamy virus bet by feline immunodeficiency virus vif yields replicative virus with novel vaccine candidate potential.

Author information

1
Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
2
Department of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center, (Deutsches Krebsforschungszentrum Heidelberg, DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany.
3
Department of Microbiology and Immunology, Western University, London, ON, Canada.
4
Department of Internal Medicine II, Division of Hematology, University Hospital of Würzburg, Würzburg, Germany.
5
Roche Pharma AG, Grenzach-Wyhlen, Germany.
6
University of Dar es Salaam, Dar es Salaam, Tanzania.
7
Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
8
Roche Glycart AG, Schlieren, 8952, Switzerland.
9
Division of Infectious Disease, University of Colorado, Anschutz Medical Campus, Aurora, USA.
10
Department of Molecular Diagnostics of Oncogenic Infections, Research Program Infection, Inflammation and Cancer, German Cancer Research Center, (Deutsches Krebsforschungszentrum Heidelberg, DKFZ), Im Neuenheimer Feld 242, 69120, Heidelberg, Germany. m.loechelt@dkfz.de.

Abstract

BACKGROUND:

Hosts are able to restrict viral replication to contain virus spread before adaptive immunity is fully initiated. Many viruses have acquired genes directly counteracting intrinsic restriction mechanisms. This phenomenon has led to a co-evolutionary signature for both the virus and host which often provides a barrier against interspecies transmission events. Through different mechanisms of action, but with similar consequences, spumaviral feline foamy virus (FFV) Bet and lentiviral feline immunodeficiency virus (FIV) Vif counteract feline APOBEC3 (feA3) restriction factors that lead to hypermutation and degradation of retroviral DNA genomes. Here we examine the capacity of vif to substitute for bet function in a chimeric FFV to assess the transferability of anti-feA3 factors to allow viral replication.

RESULTS:

We show that vif can replace bet to yield replication-competent chimeric foamy viruses. An in vitro selection screen revealed that an engineered Bet-Vif fusion protein yields suboptimal protection against feA3. After multiple passages through feA3-expressing cells, however, variants with optimized replication competence emerged. In these variants, Vif was expressed independently from an N-terminal Bet moiety and was stably maintained. Experimental infection of immunocompetent domestic cats with one of the functional chimeras resulted in seroconversion against the FFV backbone and the heterologous FIV Vif protein, but virus could not be detected unambiguously by PCR. Inoculation with chimeric virus followed by wild-type FFV revealed that repeated administration of FVs allowed superinfections with enhanced antiviral antibody production and detection of low level viral genomes, indicating that chimeric virus did not induce protective immunity against wild-type FFV.

CONCLUSIONS:

Unrelated viral antagonists of feA3 cellular restriction factors can be exchanged in FFV, resulting in replication competence in vitro that was attenuated in vivo. Bet therefore may have additional functions other than A3 antagonism that are essential for successful in vivo replication. Immune reactivity was mounted against the heterologous Vif protein. We conclude that Vif-expressing FV vaccine vectors may be an attractive tool to prevent or modulate lentivirus infections with the potential option to induce immunity against additional lentivirus antigens.

KEYWORDS:

APOBEC3; Bet function; Foamy virus; In vitro virus evolution; In vivo host factor requirement; Lentivirus; Replicating vaccine vector; Restriction factor; Superinfection; Vif function

PMID:
29769087
PMCID:
PMC5956581
DOI:
10.1186/s12977-018-0419-0
[Indexed for MEDLINE]
Free PMC Article

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