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

Abstract

BackgroundHosts 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.ResultsWe 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.ConclusionsUnrelated 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.Electronic supplementary materialThe online version of this article (10.1186/s12977-018-0419-0) contains supplementary material, which is available to authorized users.

Feline Foamy Virus is Highly Prevalent in Free-Ranging Puma concolor from Colorado, Florida and Southern California

“…FFV has not been documented to cause acute disease or easily recognized clinical signs of disease in domestic cats [2,14,30]. However, simian Foamy Virus (SFV) has been associated with accelerated SIV disease [31] and an association between FFV viral load and exogenous Feline leukemia virus (FeLV) viremia has been noted [31,32].…”

“…Sera were tested in duplicate on separate 96-well plates at 1:50 dilution using a non-quantitative GST-capture ELISA targeting the FFV Gag antigen, as previously described [14,15,16]. The ELISA has high sensitivity and specificity for the detection of FFV antibodies in naturally and experimentally infected domestic cats and has been validated against western blot [14,15,16]. This ELISA utilizes recombinant FFV Gag antigen generated from domestic cat FV sequences, which are 98% similar to the published puma FFV Gag [18,19].…”

“…A positive ELISA result was defined as having an OD absorbance over [2 × (meanGag + 3 SD)], with “meanGag” being the average negative control absorbance, and “SD” being the standard deviation of the negative control absorbance. This calculation employs very stringent cut off criteria [14,15,16], and is similar to methods of analytical detection reported by Lardeux et al (2016) [21]. OD calculation was revised for each run, assuring each analysis was compared to its own negative control.…”

“…In this study we exploited an extensive archive [13] to investigate FFV sero-prevalence and risk factors in pumas in the United States using a serologic assay validated for use in domestic cats [14,15,16]. Relationships between puma demography (e.g.…”

Bovine Foamy Virus: Shared and Unique Molecular Features In Vitro and In Vivo

“…These vectors mostly include replication-deficient gene transfer vectors generated in producer cells, but they also include replication-competent engineered viruses, which are mostly intended for life vaccine applications. Some of these vectors have been tested beyond cell cultures in small lab animals (mostly mice), but also in outbred hosts like dog (ex vivo PFV-based gene transfer vectors to treat canine leukocyte adhesion deficiency [162]) and cats (FFV-based replication-competent vaccine vectors [163,164]). The recent cloning of full-length BFV genomes that allows for cell-free transmission [14,25,26] is an important prerequisite for conducting and extending corresponding studies also for BFV.…”