Abstract
Feline immunodeficiency virus (FIV) is the feline analogue to human immunodeficiency virus (HIV) and utilizes parallel modes of receptor-mediated entry. The FIV surface glycoprotein (SU) is an important target for induction of neutralizing antibodies, and autoantibodies to the FIV binding receptor (CD134) block infection ex vivo; thus highlighting the potential for immunotherapies which utilize anti-receptor antibodies to block viral infection. To determine whether vaccination with CD134-SU complexes could induce protection against FIV infection, cats (n = 5 per group) were immunized with soluble CD134, recombinant FIV-SU protein, and/or CD134+SU complexes. Two trials were performed with different antigen combinations and vaccination schedules. In vivo generation of anti-CD134 and anti-SU IgG antibodies was measured, and in vitro neutralization assays were conducted. Immunization induced production of anti-CD134 and anti-SU antibodies that significantly inhibited FIV infection in vitro. However, no vaccine combination protected cats from FIV infection, and neat serum from vaccinated cats enhanced FIV growth in vitro. CD134+SU vaccinated cats exhibited increased CD4:CD8 ratio immediately prior to challenge, and antibodies were much more efficiently generated against vaccine by-products versus target antigens. Results suggest vaccination against viral and cryptic receptor epitopes yields neutralizing antibodies that synergistically inhibit FIV infection in vitro. Factors contributing to vaccine failure may include: (1) Heat-labile serum factors that enhance viral replication, (2) changes in circulating target cell populations induced by vaccination, and (3) weak immunogenicity of neutralizing epitopes compared to off-target vaccine components. Results reinforce the need to monitor vaccine preparation components and avoid non-specific immune stimulation during vaccination.
Highlights
Feline immunodeficiency virus (FIV) utilizes CD134 as primary binding receptor, and studies have demonstrated that binding of the CD134 receptor alters the conformation of FIV envelope protein gp[95] (SU) in a similar fashion to that, which occurs in the CD4/human immunodeficiency virus (HIV) gp[120] interaction, to promote high-affinity binding with the entry receptor CXCR4 (Fig. 1a).[13,14]
Increased levels of anti-surface glycoprotein (SU) IgG were detected in SU-huFc vaccinated and CD134+SU-huFc vaccinated cats beginning at week 4 post vaccination (Fig. 2b), and these levels differed significantly over time when compared to background levels
When serum samples were evaluated for antibodies against the huFc tag used to purify the soluble CD134 and PPR-SU rProteins in the vaccine preparation, significantly increased levels of anti-huFc IgG were detected in SU-huFc and CD134+SU-huFc vaccinated cats (p < 0.0001) which often exceeded anti-SU IgG production by more than 10-fold (Fig. 2c)
Summary
Feline immunodeficiency virus (FIV) is a naturally occurring lentivirus that is genetically similar to human immunodeficiency virus (HIV) and shares many immunopathogenic features of HIV infection.[1,2,3,4,5,6] Like HIV, FIV primarily infects and replicates within CD4+ T cells, and is characterized by progressive depletion of CD4+ T lymphocytes and an AIDS-like syndrome during natural infection of domestic cats.[7,8,9] Both lentiviruses require an initial interaction with a primary binding receptor for infection, and utilize analogous modes of receptor-mediated entry via the chemokine co-receptor, CXCR4.10–12 HIV binds to CD4+ target cells through a high-affinity interaction with the CD4 receptor that induces a conformational change in the envelope glycoprotein gp[120] to expose binding sites necessary for chemokine co-receptor binding (CXCR4 or CCR5) and subsequent fusion with the cell membrane (Fig. 1a).[10,11] FIV utilizes CD134 as primary binding receptor, and studies have demonstrated that binding of the CD134 receptor alters the conformation of FIV envelope protein gp[95] (SU) in a similar fashion to that, which occurs in the CD4/HIV gp[120] interaction, to promote high-affinity binding with the entry receptor CXCR4 (Fig. 1a).[13,14]Since the discovery of FIV, considerable effort has been directed at the development of safe vaccine strategies that can produce protective immunity in cats.[15,16] A commercially available, wholeinactivated virus vaccine containing two FIV subtypes Anti-CD134 IgG antibodies were not detected in serum from SU-huFc vaccinated or sham vaccinated study animals prior to FIV-infection (Fig. 2a).
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