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Review
. 2011 Oct 15;143(3-4):235-42.
doi: 10.1016/j.vetimm.2011.06.017. Epub 2011 Jun 12.

Restriction of the Felid Lentiviruses by a Synthetic Feline TRIM5-CypA Fusion

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Free PMC article
Review

Restriction of the Felid Lentiviruses by a Synthetic Feline TRIM5-CypA Fusion

Isabelle Dietrich et al. Vet Immunol Immunopathol. .
Free PMC article

Abstract

Gene therapy approaches to the treatment of HIV infection have targeted both viral gene expression and the cellular factors that are essential for virus replication. However, significant concerns have been raised regarding the potential toxic effects of such therapies, the emergence of resistant viral variants and unforeseen biological consequences such as enhanced susceptibility to unrelated pathogens. Novel restriction factors formed by the fusion of the tripartite motif protein (TRIM5) and cyclophilin A (CypA), or "TRIMCyps", offer an effective antiviral defence strategy with a very low potential for toxicity. In order to investigate the potential therapeutic utility of TRIMCyps in gene therapy for AIDS, a synthetic fusion protein between feline TRIM5 and feline CypA was generated and transduced into cells susceptible to infection with feline immunodeficiency virus (FIV). The synthetic feline TRIMCyp was highly efficient at preventing infection with both HIV and FIV and the cells resisted productive infection with FIV from either the domestic cat or the puma. Feline TRIMCyp and FIV infection of the cat offers a unique opportunity to evaluate TRIMCyp-based approaches to genetic therapy for HIV infection and the treatment of AIDS.

Figures

Figure 1
Figure 1
Scheme for the generation of a synthetic feline TRIM5 CypA gene fusion. As feline TRIM5 is truncated by the presence of a STOP codon in the genomic region homologous to human TRIM5 exon 8, the start codon of feline CypA was fused to the feline TRIM5 cDNA at the 3′ end of exon 6. The gene fusion site for the synthetic feline TRIMCyp is also shown in comparison with the naturally-occurring macaque and owl monkey TRIMCyps, and the synthetic human TRIMCyp (huT5-S322-Cyp) (Neagu et al., 2009).
Figure 2
Figure 2
Inhibition of FIV replication by stable expression of a synthetic feline TRIMCyp fusion protein. Duplicate cultures of CrFK cells were transduced with retroviral vectors bearing feline TRIMCyp (TRIMCyp6 and TRIMCyp7) and stably selected. TRIMCyp-expressing or vector-only control (CON) cells were then infected with FIV-Fca (Petaluma) or FIV-Pco (COLV). Viral growth was monitored by non-isotopic reverse transcriptase assay.
Figure 3
Figure 3
Stable expression of feline TRIMCyp inhibits viral entry. CrFK cells stably transduced with feline TRIMCyp expression vectors (TRIMCyp6&7) or vector only (CON) were infected with HIV(VSV) or FIV(VSV)-GFP pseudotypes and viral entry quantified by flow cytometry (mean percentage, n=3,+/−SE). Infection with either FIV or HIV-based pseudotypes was reduced significantly by feline TRIMCyp.

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