• Olive Leaf and FIV


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  • Olive leaf extract (OLE) is about as close to the perfect herbal supplement for an FIV+ cat as it is possible to get. Its downside is that of many herbal supplements: it has a strong taste that would probably not be tolerated by most cats. Although no research appears to have been done to dateof olive leaf as an FIV therapy, research as an HIV therapy has been so promising that researchers have pointed to the possibility of creating new HIV drugs based on synthetic derivatives [1]. A 2003 study demonstrated that the active ingredient in olive leaf, oleuropein, is a potent inhibitorof both free viral and cell-to-cell transmission of HIV; that it restores patterns of cellular signaling to a pre-infection state; and that it upregulates proteins that inhibit "apoptosis" (cellular self-destruction) caused by viral exposure [2]. Olive leaf was first touted in the 1990's as an inhibitor of the enzyme reverse transcriptase (RT), which retroviruses like HIV and FIV use to translate their RNA genome into DNA for insertion into the DNA of the infected cell. This view has uncertain origins and seems to be rooted in a study dating from 1998 which is, unfortunately, unavailable for inspection [3]. It later became clear that viral inhibition occurred at other points of the replication process. A number of more recent published studiesidentify oleuropein and its metabolite hydroxytyrosol (HT) as HIV inhibitors at both the fusion and integration stages. This puts oleuropein and HT among a very select group of molecules capable of multiple actions against retroviruses.

  • Oleuropein and hydroxytyrosol accomplish fusion inhibition by binding the viral envelope transmembrane protein responsible for fusion with the target cell [4]. Upon viral binding of the outer envelope protein to the cellular receptor, the inner transmembrane protein of the envelope is induced to assume a helical (6HB) formation that permits viral entry to the target cell membrane. Exposure to oleuropein and HT prevents this helical formation from occurring. Oleuropein and HT are small molecules with low molecular weight and demonstrate the ability of small molecules to block formation of the protein-protein complexes that enveloped viruses such as HIV and FIV depend on.

  • Oleuropein and HT also inhibit the viral enzyme integrase at three separate points of activity: processing, strand transfer (integration) and disintegration [5]. Processing of the 3' (the so-called "3-prime end" of a DNA strand, where linkages to complementary 5' ends of other strands of cellular nucleotides characteristically occur) by integrase deletes several nucleotides to facilitate docking of viral DNA. Oleuropein inhibits this processing. It also inhibits the actual transfer of the viral DNA strand, as well as the process of "disintegration," the actual cleavage and closing of the rift in the cellular genome after integration of the viral DNA. In addition to catalysing the integration of viral DNA into the host cell genome, integrase also plays an important role during the reverse-transcription step of the viral life cycle through physical interactions with reverse-transcriptase. Oleuropein and HT interact with the protein recognition interface of the virus in a region called the C-terminal, restricting its ability to interact with reverse transcriptase. This is the likely source of the original identification of OLE as an RT inhibitor. In other words, it affects reverse transcription indirectly via integrase inhibition rather than directly.

  • A report presented at the 2004 International Conference on AIDS confirms that OLE does not interact with antiretroviral drugs commonly used to treat HIV. "Combination antiviral assays demonstrate that OLE exhibits synergistic interactions with both AZT and 3TC. The synergism between OLE and 3TC is about 10-fold greater than that between OLE and AZT. Conclusion: This is the first characterization of the anti-HIV activity of OLE. Our results demonstratesynergism between OLE and HAART. This information should help in rational design of HIV treatment regimens that incorporate OLE" [6]. A writer on the alternative treatment Keep Hope Alive website claims that two people using OLE as monotherapy reported a viral load that dropped, then rose again after several months, suggesting that perhaps the virus mutates and overcomes inhibition. This is known to happen with several other natural compounds, such as l-chicoric acid, a substance found in green coffee beans. However, other anecdotal accounts mention a fall without a subsequent rise. Of course, there is no guarantee that OLE also inhibits FIV, but many substances that inhibit HIV enzymes are known to inhibit the same enzymes in FIV. This is true not only of nucleosides that inhibit HIV reverse transcription, but also of newer HIV integrase inhibitors. FIV integrase has a 37% homology (identity) in amino acid sequence to its HIV counterpart [7]. Limited evidence provided by a private owner (see Reports) seems to confirm the ability of OLE to significantly inhibit FIV, most probably at the integration stage.

  • Olive leaf has many other potentially useful properties. It is a potent antioxidant that placed second only to resveratrol, the antioxidant in the skin of red grapes, in a recent trial [8]. Antioxidants are key to a variety of beneficial immune processes. OLE is also a natural antibiotic, with documented action against many bacteria (e.g., e coli) and fungi (e.g., candida albicans) [9]. Since FIV can open a pathway to infection with bacteria and fungi, this activity has some significance. OLE has also been used to control blood sugar in diabetic animals [10] and blood pressure in animals with high blood pressure [11].

  • Any vet should be able to vouch for the safety of olive leaf. It comes in several brand names for animal use (e.g., Olivet, Olipet) which should be dependable. It is important, though, to use products with the highest possible oleuropein content. No product listing less than 15% on the labeling should be used. Unfortunately, regardless of the capsule dosage, the capsules often tend to be large and dog-sized, so that the contents must either be repacked in smaller capsules or emptied out for whatever other kinds of administration is envisioned.
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  • References:

  • [1] Lee-Huang, S and eight more. Compositions and methods for treating obesity, obesity related disorders and for inhibiting the infectivity of human immunodeficiency virus, Feb 16, 2011.
  • http://www.google.com/patents/US8574635

  • [2] Lee-Huang S, Zhang L, Huang PL, Chang YT, Huang PL. Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment. Biochem Biophys Res Commun. 2003 Aug 8;307(4):1029-37.
  • http://www.ncbi.nlm.nih.gov/pubmed/12878215

  • [3] Ng TB, et al (1997) Anti-HIV natural products with special emphasis on HIV reverse transcriptase inhibitors, Life Sci 61 (10): 933-49.

  • [4] Bao J, Zhang DW, Zhang JZ, Huang PL, Huang PL, Lee-Huang S. Computational study of bindings of olive leaf extract (OLE) to HIV-1 fusion protein gp41. FEBS Lett. Jun12;581(14):2737-42.
  • http://www.ncbi.nlm.nih.gov/pubmed/17537437

  • [5] Lee-Huang S, Huang PL, Zhang D, Lee JW, Bao J, Sun Y, Chang YT, Zhang J, Huang PL. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: part II. integrase inhibition. Biochem Biophys Res Commun. 2007 Mar 23;354(4):879-84.
  • http://www.ncbi.nlm.nih.gov/pubmed/17261269

  • [6] Lee-Huang S, Huang P, Huang P. Anti-HIV activity of olive leaf extract and synergism with HAART. Int Conf AIDS. 2004 Jul 11-16; 15: abstract no. WePeA5651.
  • http://gateway.nlm.nih.gov/MeetingAbstracts/102283585.html

  • [7] Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, and Poeschla EM. LEDGF/p75 Determines Cellular Trafficking of Diverse Lentiviral but Not Murine Oncoretroviral Integrase Proteins and Is a Component of Functional Lentiviral Preintegration Complexes. J. Virol. September 2004 vol. 78 no. 17 9524-9537.
  • http://jvi.asm.org/content/78/17/9524.full

  • [8] O'Brien NM, Carpenter R, O'Callaghan YC, O'Grady MN, Kerry JP. Modulatory effects of resveratrol, citroflavan-3-ol, and plant-derived extracts on oxidative stress in U937 cells. J MedFood. 2006 Summer;9(2):187-95.
  • http://www.ncbi.nlm.nih.gov/pumed/16822204

  • [9] Markin D, Duek L, Berdicevsky I. In vitro antimicrobial activity of olive leaves. Mycoses. 2003 Apr;46(3-4):132-6.
  • http://www.ncbi.nlm.nih.gov/pubmed/12870202

  • [10] Jemai H, Feki A, Sayadi S. Antidiabetic and antioxidant effects of hydroxytyrosol and oleuropein from olive leaves in alloxan-diabetic rats. J Agric Food Chem. 2009 Oct 14;57(19):8798-804.
  • http://www.ncbi.nlm.nih.gov/pubmed/19725535

  • [11] Khayyal MT, el-Ghazaly MA, Abdallah DM, Nassar NN, Okpanyi SN, Kreuter MH. Blood pressure lowering effect of an olive leaf extract (Olea europaea) in L-NAME induced hypertension in rats. Arzneimittelforschung. 2002;52(11):797-802.
  • http://www.ncbi.nlm.nih.gov/pubmed/12489249

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