Feline Immunodeficiency Virus (FIV) Peptide、貓免疫缺陷病毒肽的介紹

Definition

Feline immunodeficiency virus (FIV) is an important viral pathogen worldwide in the domestic cat, which is the smallest animal model for the study of natural lentivirus infection. FIV peptide vaccines comprising immunodominant FIV epitopes have better cellular and humoral immune responses over inactivated or attenuated virus vaccines.

Discovery

There have been a number of reports on the identification of immunodominant viral epitopes. Lombardi, S et al., in 1993 identified a linear neutralization site within the third variable region of the FIV envelope. Epitope mapping studies using synthetic peptides or overlapping fragments of the envelope protein of FIV have revealed immunodominant neutralization sites within the third variable (V3) region of the envelope glycoprotein. Another immunodominant domain, comprising a loop of five to seven amino acids between two conserved cysteine residues, has been identified within the transmembrane (TM) envelope glycoproteins of FIV and HIV-1. The p24 capsid protein of FIV also contains an immunodominant epitope which elicits a Gag-specific CTL response and induces anti-p24 antibodies when used as an immunogen in cats 1,2,3.

Structural Characteristics

To induce a broader spectrum of virus-specific immune responses in the host several synthetic peptides containing immunodominant FIV epitopes from the Env V3 domain, TM glycoprotein, and p24 capsid protein have been synthesized. To improve the conformational stability of the peptide immunogen, these FIV peptides were linked by proline residues and synthesized with carboxy- and amino-terminal cysteine residues enabling the peptide to form multimers or to cyclize 4.

A series of norstatine-based HIV/FIV protease inhibitors incorporating a 15-membered macrocycle as a mimic of the tri-peptide (Ala-Val-Phe), a motif with a small P3' residue effective against the FIV protease and the drug-resistant HIV proteases, has been synthesized. It was found that the macrocycle is important to the overall activity of the inhibitors. Certain inhibitors were developed expressing low nanomolar inhibitory activity against the HIV/FIV proteases and they are also effective against some drug-resistant as well as TL3-resistant HIV proteases 5.

Mode of Action

FIV is an important viral pathogen worldwide in the domestic cat, which is the smallest animal model for the study of natural lentivirus infection. FIV has an overall genome size similar to HIV, the causative agent of AIDS in man, and shares with the human virus genomic features that may serve as common targets for development of broad-based intervention strategies. Specific targets include enzymes encoded by the two lentiviruses, such as protease (PR), reverse transcriptase (RT), RNAse H, and integrase (IN). In addition, both FIV and HIV encode Vif and Rev elements essential for virus replication and also share the use of the chemokine receptor CXCR4 for entry into the host cell  6.

Cats were immunized with a 46-residue multiepitopic synthetic peptide of FIV comprising immunodominant epitopes present in the third variable domain of the envelope glycoprotein, transmembrane glycoprotein, and p24 Gag core protein, using Quil A as an adjuvant. All vaccinated cats developed a humoral response which recognized the synthetic peptide immunogen and the intact viral core and envelope proteins. A FIV Gag- and Env-specific effector cytotoxic T-lymphocyte response was also detected, which peaked at week 30. This response appeared to be major histocompatibility complex restricted. Epitope mapping studies revealed that both the cellular and humoral immune responses were directed principally to a peptide within the TM glycoprotein 4.

Functions

Neutralizing monoclonal antibody, Peptides corresponding to three domains of the envelope glycoproteins of FIV used to immunize cats. This peptide is located in the membrane-proximal region of the extracellular domain. These results suggest that lentivirus transmembrane glycoproteins share a determinant in the juxtamembrane ectodomain which could be of importance in the design of vaccines against AIDS 7.

B cell epitopes, the battery of synthetic peptides was then used to immunize outbred Swiss mice in the attempt to reveal other potential sites of immunogenicity of the Env glycoproteins. Analysis of peptide-immunized mouse sera for anti-peptide reactivity revealed more numerous B cell epitopes, generally mapping in different peptides, as compared with those defined in the feline system. None of the mouse anti-peptide sera, however, proved neutralizing for FIV-Pet 8.

Env gene of FIV, the Env protein gives, after cleavage, 2 glyco-protein fragments referred to as SU (surface glycoprotein) and TM (transmembrane glycoprotein), in which nine domains, comprising continuous B epitopes of the envelope glycoproteins of the FIVs and recognized during the natural infection 9.

References

1. Lombardi S, Garzelli C, Rosa CL, Zaccaro L, Specter S, Malvaldi G, Tozzini F,  Esposito F, Bendinelli M (1993). Identification of a linear neutralization site within the third variable region of the feline immunodeficiency virus envelope. J. Virol., 67: 4742–4749.

2. Flynn JN, Cannon CA, Beatty J, Mackett M, Rigby M, Neil JC, Jarrett O(1994). Induction of feline immunodeficiency virus-specific cytotoxic T cells in vivo with carrier-free synthetic peptide. J. Virol., 68:5835–5844.

3. Pancino G, Camoin L, Sonigo P (1995). Structural analysis of the principal immunodominant domain of the feline immunodeficiency virus transmembrane glycoprotein. J. Virol., 69:2110–2118.

4. Flynn JN, Cannon CA, Neil JC, Jarrett O (1997). Vaccination with a feline immunodeficiency virus multiepitopic peptide induces cell-mediated and humoral immune responses in cats, but does not confer protection. J Virol., 71(10):7586–7592.

5. Mak CC, Le VD, Lin YC, Elder JH, Wong CH (2001). Design, synthesis, and biological evaluation of HIV/FIV protease inhibitors incorporating a conformationally constrained macrocycle with a small P3' residue. Bioorganic & Medicinal Chemistry Letters, 11(2):219-222.

6. Elder JH, Sundstrom M, de Rozieres S, de Parseval A, Grant CK, Lin YC (2008). Molecular mechanisms of FIV infection. Veterinary Immunology and Immunopathology, 123(1-2):3-13.

7. Richardson J, Moraillon A, Crespeau F, Baud S, Sonigo P, Pancino G (1998). Delayed infection after immunization with a peptide from the transmembrane glycoprotein of the feline immunodeficiency virus. J Virol., 72(3):406-2415.

8. Massi C, Lombardi S, Indino E, Matteucci D, La Rosa C, Esposito F, Garzelli C, Bendinelli M (1997). Most potential linear b cell epitopes of env glycoproteins of feline immunodeficiency virus are immunogenically silent in infected cats. AIDS Research and Human Retroviruses, 13(13):1121-1129.

9. Pancino G, Chappey C, Saurin W, Sonigo P (1993). B epitopes and selection pressures in feline immunodeficiency virus envelope glycoproteins. J. Virol., 67:664-672.