Interferon and FIV



  • 1. Introduction

  • 2. What Interferons Do and Don’t Do

  • 3. Possible Downsides

  • 4. Injectable Human Interferon for HIV

  • 5. Human Interferon for FIV

  • 6. Feline Omega Interferon for FIV

  • 7. Closing Observations


  • Click here to open a Glossary of Terms in a separate window.

  • This document deals with interferons only in relation to retroviral infections. (For clinical use information, see “Bud's Medications and Supplements”.) Interferons as therapy for diseases often associated with FIV infection can be found on pages of this site that deal with those illnesses. (See the “FIV and Upper Respiratory Infection” and “FIV and Gingivostomatitis” pages.) References follow individual sections rather than appearing at the end.

  • 1. Introduction

  • Interferons are part of the immune system’s front line defense against viruses, and from the earliest days of HIV therapy there has been a significant amount of research into the possible uses of pharmaceutical interferon. The results to date have been checkered – checkered enough that interferons still have no recognized role in the clinical treatment of HIV infection. The same cannot be said for treatment of FIV, since Virbac’s feline omega interferon (Virbagen Omega) is currently the most widely recognized high-end FIV therapy outside of North America, with oral human interferon therapy widely practiced, as well. This discrepancy makes the relationship of interferons to HIV/FIV and their applicability as therapy for both worth some scrutiny.

  • Interferons are natural substances manufactured by leukocytes (white cells) of mammalian immune systems. They are classified as either Type 1 or Type 2 (although a newly discovered lambda-interferon has been designated Type 3).

  • Only one interferon occupies the Type 2 category. It is called interferon-gamma (IFN-γ), and its use is exclusively as a signaling protein within the complex crosstalk that switches immune cells on and off, and tells them what to attack and what not to attack. A very important signaling protein, it might be added, since IFN-γ, manufactured by Natural Killer lymphocytes of the natural immune system and the T Helper 1 subset of T lymphocytes that directs the cell-mediated immune response, is central to an antiviral response. Here an interesting discrepancy presents itself. HIV, as part of its strategy to shut down an effective cell-mediated immune response, depletes lymphoid tissue of IFN-γ [Murray]. Conversely, IFN-γ is found in abundance in the lymphoid tissue of FIV-infected cats [Orandle]. Although, like HIV, FIV depletes other TH1 signaling proteins (most notably the Interleuken-2 necessary to T cell activation, maturation, and proliferation), the difference with regard to IFN-γ suggests that there are some different disease dynamics at work and reminds us that, for all of their similarities, FIV and HIV are different viruses that produce different disease. Particularly intriguing is the question whether the abundance of IFN-γ in the lymphoid tissue of FIV-infected cats points to a different strategy of attack on the immune system and, if so, what implications there might be for therapy. Exogenous (i.e., supplied externally as a pharmaceutical) IFN-γ has shown no useful activity against FIV [Yamamoto].

  • The major Type 1 interferons are interferon-alpha (IFN-α) and interferon-beta (IFN-β), although there are a number of other Type 1 interferons whose function is not always well understood. Among these are interferon-omega (IFN-ω). Type 1 interferons have two major functions. Like IFN-γ, IFN-α and IFN-β are signaling proteins which have complementary receptors on a variety of leukocytes to govern their behavior. In other words, they have an immunomodulating role. Type 1 interferons have a second function, however, which is directly antiviral, inhibiting the ability of viruses to replicate in infected cells.

  • HIV research has focused largely on pharmaceutical IFN-α as a therapeutic. IFN-α has more than a dozen molecular subtypes. Interferons produced by recombinant DNA technology (e.g., Intron and Roferon, the latter discontinued) are replicants of a single subtypes. Less explored as HIV therapies, “natural” pharmaceutical interferons contain a range of IFN-α subtypes and are manufactured from cultured cell lines rather than by DNA recombination. Virbagen Omega, the veterinary interferon, is a recombinant product. Early research into possible pharmaceutical uses of interferon for veterinary purposes found that the native omega Type 1 interferon (IFN-ω) was more bioactive in cats than its alpha counterpart [Virbagen]. Recent unpublished in vitro study of FeLV-infected feline cells found feline IFN-ω 50 to 90 times more potent than human IFN-α [Domenech], although this finding would not include the immunomodulating benefit of either. Interferons are bioactive across species boundaries so that human interferon-alpha (HuIFN-α) can be used to treat cats and feline interferon-omega can be used to treat dogs. However, this cross-species bioactivity has been of limited usefulness to cats since the human origin of the interferon provokes an “alien antigen” antibody response in cats that renders high therapeutic doses useless within three to seven weeks [Zeidner]. The decision was therefore made to produce a feline IFN-ω for therapeutic use.

  • _____________________________________________________________________
  • References – Part 1

  • Domenech A, Miro G, Collado VM, Ballesteros N, Sanjosé L, Escolarb E, Martin S, Gomez-Lucia E. Use of recombinant interferon omega in feline retrovirosis: From theory to practice. Veterinary Immunology and Immunopathology 143 (2011) 301-306.
  • http://www.ncbi.nlm.nih.gov/pubmed/21719116
  • Murray HW, Hillman JK, Rubin BY, Kelly CD, Jacobs JL, Tyler LW, Donelly DM, Carriero SM, Godbold JH, and Roberts RB. Patients at risk for AIDS-related opportunistic infections. Clinical manifestations and impaired gamma interferon production. N Engl J Med. Volume 313:1504-1510 December 12, 1985 Number 24.
  • http://www.ncbi.nlm.nih.gov/pubmed/3934537
  • Orandle MS, Crawford PC, Levy JK, Udoji R, Papadi GP, Ciccarone T, Mergia A, Johnson CM.. CD8+ thymic lymphocytes express reduced levels of CD8beta and increased interferon gamma in cats perinatally infected with the JSY3 molecular clone of feline immunodeficiency virus. AIDS Res Hum Retroviruses. 2000 Oct 10;16(15):1559-71.
  • http://www.ncbi.nlm.nih.gov/pubmed/11054269
  • Virbagen Omega®: The Potential of a Veterinary Interferon.
  • petdental.com.au/Conference%20Papers/Virbagen%20Omega.
  • Yamamoto JK and Tanabe T. Feline immunodeficiency virus lacks sensitivity to the antiviral activity of feline IFN-gamma. J Interferon Cytokine Res. 2001 Dec; 21(12):1039-46 2001.
  • http://www.ncbi.nlm.nih.gov/pubmed/11798461
  • Zeidner NS, Rose LM, Mathiason-DuBard CK, Myles MH, Hill DL, Mullins JI, Hoover EA.Zidovudine in combination with alpha interferon and interleukin-2 as prophylactic therapy for FeLV-induced immunodeficiency syndrome (FeLV-FAIDS). J Acquir Immune Defic Syndr. 1990;3(8):787-96.
  • http://www.ncbi.nlm.nih.gov/pubmed/2164083
  • ______________________________________________________________________

  • 2. What Interferons Do and Don’t Do

  • Most of the mode of action of feline omega interferon, both generally and with regard to FIV, has been inferred from research with human alpha interferon. This is somewhat problematical since they are different interferons, different creatures, and different diseases. It is a pretty safe bet, though, that in both cases, the activity of interferons is both directly antiviral and indirectly immunomodulating. “IFN-α plays a very important role in the host antiviral defense by directly inhibiting the intracellular-viral lifecycle or by regulating the immune-system T-cell response during viral infection. IFN-α, -ß, and -γ, together and separately, inhibit most stages of replication and the lifecycle of a wide variety of viruses” [Brassard]. Human genes contain more than 100 interferon response elements (ISRE) that, when activated and transcribed, account for a broad range of immune activities.

  • Direct Antiviral Effects

  • IFNs are known to have antiretroviral properties, interfering with different steps of the retroviral replication cycle, apart from any modulating effect on the immune system. During acute infection they inhibit the activity of viral Messenger RNA (mRNA) during both the reverse transcription of viral RNA to DNA for insertion into cellular genes and again during the translation of the virus back into RNA when the genes are activated. (For a step by step description of the FIV life cycle, see Bud’s Therapeutic Guidelines.) However--and of most therapeutic relevance--in the chronically infected cells of hosts with established disease, the direct antiviral action seems to occur almost exclusively at the late stage of viral budding and release [Coccia], a view reflected by unpublished findings derived from in vitro study of feline IFN-ω [Domenech]. At least one aspect of this inhibition has recently been discovered to lie in IFN-α’s upregulation (stimulation) of a protein, “which binds newly formed retroviruses to the cell surface. In cells which are actively expressing these proteins (dubbed ‘tetherins’), newly budded virions can be seen to cluster densely just outside the cell membrane and remain there, rather than being released into the body to serve as new infectious particles” [Perez-Caballero]. HIV has evolved a gene called VPU for negating the action of tetherin. Until recently it was unclear how adaptable the human model is (or isn’t) to cats, since FIV does not have a VPU gene and there was no research on tetherin in felines. A recently published study has established that feline tetherin is indeed inducible by both IFN-α and -ω, displayed potent inhibition of FIV in vitro, and had no natural viral antagonist analogous to HIV VPU. However, when expressed in feline cell lines, tetherin did not, surprisingly, inhibit the replication of FIV. It's budding- inhibitory effect was counterbalanced -- and then some -- by its evident furthering of the process of “syncytium formation,” the name given to the clumping of infectable cells that permits direct cell-to-cell viral transmission. Concluded researchers, “Thus, while tetherin may prevent the release of nascent viral particles, cell to cell spread remains efficient in the presence of abundant viral receptors and tetherin up-regulation may enhance syncytium formation. Accordingly, tetherin expression in vivo may promote the selective expansion of viral variants capable of more efficient cell to cell spread.” [Dietrich]. This discovery probably explains the observation of earlier HIV researchers that IFN-α did not inhibit direct cell-to-cell transfer of virus, as distinct from the release of new virus into plasma [Vendrame]. One mark of disease advancement is the increase in direct transmission of virus across cell membranes between healthy and infected cells in direct contact with one another, one of several facts which might or might not argue for early use of therapeutic interferon.

  • There is an additional caveat regarding the direct antiviral action of interferon. Although interferon inhibits the release of complete virions (new protoviruses), it does not inhibit the release of viral genetic particles (envelope proteins from the ENV gene and p24 capsid protein from the GAG gene) [Fernie]. The evolving understanding of the detrimental effects of HIV and FIV has strongly implicated the effect of viral particles on healthy cells, as opposed to actual infection of same.

  • Immunomodulating Effects

  • In the laboratory, interferon-α has shown many effects on the immune system of potential benefit in fighting HIV, and by extension FIV [Brassard][Essers][Shirazi][Lapenta]. Among these:

  • --IFN-α primes the immune response, stimulating Natural Killer (NK) lymphocytes of the innate immune response, shaping the subsequent innate and adaptive responses to viral infection, and facilitating the shift from the first to the second.

  • --IFN-α stimulates the proliferation, activation, and generation of existing CD8+ cytotoxic T cells (CTLs)–and particularly CD8+ memory T cells that archive ready-response information– considered crucial to effective control of HIV and FIV infection.

  • --IFN-α promotes TH1/TH2 balance by inducing differentiation of naive T cells into the T-Helper 1 subset that orchestrates the cell-mediated mediated (T cell) immune response. HIV and FIV both depress T cell response in favor of an antibody- (B cell) weighted response by promoting dominance of the T-Helper 2 subset.

  • --IFN-α inhibits (downregulates) T cell surface expression of receptors for the host chemokine co-receptor CXCR4 that allows virus-to-cell and cell-tocell attachment and that mediates a number of HIV’s and FIV’s harmful host interactions.

  • --IFN-α enforces cell quiescence in the absence of antigen and inhibits the “apoptosis” (programmed cell death) that HIV and FIV induce.

  • --IFN-α promotes the productive action of stem cells in the bone marrow that is inhibited by FIV and HIV.

  • ________________________________________________________________________
  • References – Part 2

  • Brassard DL, Grace MJ and Bordens RW. Interferon- as an immunotherapeutic protein . Journal of Leukocyte Biology. 2002;71:565-581.
  • http://www.jleukbio.org/cgi/content/full/71/4/565?ijkey=c1f51a83e788f635c678ef37db789194d6ff42db
  • Coccia EM, Krust B and Hovanessian AG. Specific inhibition of viral protein synthesis in HIV-infected cells in response to interferon treatment. September 16, 1994 The Journal of Biological Chemistry, 269, 23087-23094.
  • http://www.jbc.org/content/269/37/23087.full.pdf+html
  • Dietrich I, McMonagle EL, Petit S, Vijayakrishnan S, Logan N, Chan CN, Towers GJ, Hosie MJ, and Willett BJ . Feline tetherin (BST-2) efficiently restricts feline immunodeficiency virus release but not spreading infection. J. Virol. 10.1128. Published online ahead of print on 13 April 2011.
  • http://jvi.asm.org/cgi/content/abstract/JVI.00071-11v1
  • Domenech A, Miro G, Collado VM, Ballesteros N, Sanjosé L, Escolarb E, Martin S, Gomez-Lucia E. Use of recombinant interferon omega in feline retrovirosis: From theory to practice. Veterinary Immunology and Immunopathology 143 (2011) 301-306.
  • http://www.ncbi.nlm.nih.gov/pubmed/21719116
  • Essers M, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, and Trumpp A. IFNa activates quiescent HSCs in vivo. Nature, online published on 11 February 2009; DOI:10.1038/nature07815
  • http://news.biocompare.com/News/NewsStory/262987/NewsStory.html
  • Fernie BF,' Poli G, and Fauci A. Alpha Interferon Suppresses Virion but Not Soluble Human Immunodeficiency Virus Antigen Production in Chronically Infected T-Lymphocytic Cells. Journal of Virology, July 1991, p. 3968-3971
  • Lapenta C, Santini SM, Proietti E, Rizza P, Logozzi M, Spada M, Parlato S, Fais S, Pitha PM, Belardelli F. Type I interferon is a powerful inhibitor of in vivo HIV-1 infection and preserves human CD4(+) T cells from virus-induced depletion in SCID mice transplanted with human cells. Virology. 1999 Oct 10;263(1):78-88.
  • Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, Bieniasz PD.. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell. 2009 Oct 30;139(3):499-511.
  • Shirazi Y, Pitha PM. Interferon downregulates CXCR4 (fusin) gene expression in peripheral blood mononuclear cells. J Hum Virol. 1998 Jan-Feb;1(2):69-76.
  • http://www.ncbi.nlm.nih.gov/pubmed/10195234?dopt=Abstract
  • Vendrame D, Sourisseau M, Perrin V, Schwartz O, Mammano F.J. Partial inhibition of human immunodeficiency virus replication by type I interferons: impact of cell-to-cell viral transfer. Virol. 2009 Oct;83(20):10527-37. Epub 2009 Aug 12.
  • http://www.ncbi.nlm.nih.gov/pubmed/19706714

  • _______________________________________________________________________

  • 3. Possible Downsides

  • Although positive laboratory findings about interferon are numerous, studies have also turned up troubling aspects of alpha interferon in the pathogenesis of HIV that have led to questions about it appropriateness as a long-term therapeutic agent. No one questions the fact that IFN-α has paid its way in treatment of diseases (such as hepatitis B and Kaposi’s sarcoma) that are often fellow travelers with HIV and that complicate the lives of HIV-infected people; the same might be said for feline IFN-ω, which has proved of immense help in treating the oral inflammatory disease that so often accompanies FIV infection. The cause for pause has come with discoveries about the particular interplay between IFN-α and the human immunodeficiency virus, which paradoxically seems both beneficial and detrimental. What might the explanation be?

  • Research has struggled to understand the significance of the fact that IFN-α levels, almost undetectable in the serum of healthy individuals, are high in acute infection and later increase with disease progression. A number of studies have focused on a particular set of immune cells called type 2 predendritic cells (preDC2), which were found to be powerhouse sources of IFN-α in the human immune system, producing 200 to 1000 times more than any other immune cell. Dendritic cells are the chief antigen-presenting cells of mammalian immune systems. They capture particles of alien invaders and present them on their surface to T-cells using MHC (major histocompatability complex) molecules so the T cells can configure an appropriate response. In HIV-infected individuals, increased MHC I expression has been directly correlated with depletion of immature T cells (thymocytes) and HIV pathogenesis. IFN-α secreted by preDC2 is directly responsible for MHCI upregulation in the infected thymus. HIV, however, has the ability to hijack the process. PreDC2 stimulated by exposure to the virus upregulate MHC I molecules [Keir], whose interaction with thymocytes in the infected thymus disrupts the process of T cell selection, resulting in both negative selection (and deletion) and interruption of normal maturation of T and Natural Killer lymphocytes [Uittenbogaart ][Gurney]. A different line of research has also cast interferons in a questionable light. HIV infection, it was found, drives expression of sialoadhesin, a cell-adhesion molecule, in monocytes, a type of nonlymphoid immune cell. Expression of sialoadhesin correlates with viral load in the peripheral blood, perhaps because it binds HIV-1 and effectively facilitates infection of other cells that interact with monocytes. Interferons, including IFN-α, are primary inducers of sialoadhesin expression in monocytes [Rempel].

  • In another study, levels of IFN-α in lymph nodes were found to increase in direct proportion to disease progression [Durudas]. One fascinating study focusing on why African green monkeys infected with simian immunodeficiency virus (SIV) do not develop chronic immune activation and AIDS, despite viral loads similar to those detected in rhesus macaques which do, found that while a strong upregulation of type I IFN–stimulated genes occurred in both species, gene expression returned to basal levels after day 28 post-infection in the green monkeys but was sustained in the rhesus macaques [Jacquelin]. So either retroviruses are using the normal antiviral capacities of interferon to enhance their survival, or unexplained factors are advancing the process, with interferon production being dragged along in an escalating effort to control it.

  • Various explanations have been offered for why IFN-α has seemed simultaneously helpful and harmful, and why internally produced IFN-α fails to control HIV and some SIV infection – and in some ways seems to further it. Whether the body’s own inadequate interferon production and pharmaceutically-introduced interferon are directly comparable in this regard remains to be seen.

  • _____________________________________________________________________
  • References – Part 3

  • Berglund O, Engman K, Ehrnst A, Andersson J, Lidman K, Akerlund B, Sönnerborg A, Strannegård O. Combined treatment of symptomatic human immunodeficiency virus type 1 infection with native interferon-alpha and zidovudine. J Infect Dis. 1991 Apr;163(4):710-5.
  • http://www.ncbi.nlm.nih.gov/pubmed/1672701
  • Durudas A, Milush JM, Chen HL, Engram JC, Silvestri G, Sodora DL. Elevated levels of innate immune modulators in lymph nodes and blood are associated with more-rapid disease progression in simian immunodeficiency virus-infected monkeys. J Virol. 2009 Dec;83(23):12229-40.
  • Gurney KB, Colantonio AD, Blom B, Spits H, and Uittenbogaart CH. Endogenous IFN- Production by Plasmacytoid Dendritic Cells Exerts an Antiviral Effect on Thymic HIV-1 Infection. The Journal of Immunology, 2004, 173: 7269-7276.
  • http://www.jimmunol.org/cgi/content/full/173/12/7269
  • Jacquelin B et al. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J. Clin. Invest. 119(12): 3544-3555 (2009).
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786805/?
  • Keir ME, Stoddart CA, Linquist-Stepps V, Moreno ME, and McCune JM. IFN- Secretion by Type 2 Predendritic Cells Up-Regulates MHC Class I in the HIV-1-Infected Thymus. The Journal of Immunology 2002, 168:325–331.
  • http://www.jimmunol.org/cgi/reprint/168/1/325.
  • Rempel H, Calosing C, Sun B, Pulliam L. Sialoadhesin Expressed on IFN-Induced Monocytes Binds HIV-1 and Enhances Infectivity. PLoS One. 2008 Apr 16;3(4):e1967.
  • http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0001967
  • Uittenbogaart CH. HIV And Plasmacytoid Dendritic Cells In The Thymus. Grant 5R01AI052002-04 from National Institute Of Allergy And Infectious Diseases.
  • http://www.researchgrantdatabase.com/g/5R01AI052002-04/HIV-and-Plasmacytoid-dendritic-cells-in-the-thymus/
  • ______________________________________________________________

  • 4. Injectable Human Interferon for HIV

  • Early trials of IFN-α as HIV therapy showed inconsistent results. In one such trial, patients with advanced HIV- infection who had been taking AZT received IFN-α daily for 3 months. On a hopeful note, significantly decreased levels of infectious virus were observed in six of eight patients treated with IFN and AZT, but in only one of nine patients treated with AZT alone. After termination of IFN-α, there was a significant rise of p24 viral antigen levels. Discouragingly, though, during IFN treatment, counts of the CD4+ cell whose loss correlates directly with immune deficiency showed an increased rate of decline. Despite its anti-HIV effect , IFN-α did not seem to be an effective “booster” treatment for severely immunodeficient patients on AZT therapy [Berglund]. In a second trial, CD4+ lymphocyte percentages were sustained at or above the baseline level during the treatment period in patients receiving IFN-α and declined slightly in patients receiving placebo. No patients in the interferon group (followed for 5 to 33 months after the study) developed an AIDS-defining opportunistic infection, compared with 5 patients in the placebo group. In both studies, side effects were unexpectedly severe. Thirty-five percent of patients assigned to receive interferon in the second study withdrew because of toxicity [Lane].

  • More recent trials have been more hopeful. In 2001, IFN-α appeared again on the HIV radar via improved and reformulated “pegylated” interferon-alpha (PEG-IFN-α). Pegylating involves formulating with polyethylene glycol to extend the period of drug clearance. PEG-IFN-α (Pegasys has replaced Roferon and Peg-Intron has been added to to the Intron menu) can be injected just once a week, and at lower doses than was formerly the case. This makes the drug somewhat more tolerable, and removes one of the primary impediments to its use as HIV therapy – its inconvenience and some of its potential side effects. A study published in AIDS showed that PEG-IFN-α had both antiviral and immunostimulating activity and reduced viral load by more than 0.5 log, sustained over 12 weeks in patients on Highly Active Anti-Retroviral Therapy (aka “the cocktail”) with stable but detectable viral load [Emilie]. In a 2003 presentation it was reported that ten asymptomatic, therapy naive German patients who received low-dose (80 microgram) PEG-IFN-α once a week for 24 weeks experienced a gain of between 92-208 CD4+ cells and a decline of between 0.8 and 1.3 logs (average decrease from 4.1 to 3.1 log) HIV RNA viral load.. Despite a few adverse effects, side-effects were generally tolerable [Schugt]. The lower-than-usual dosage is an intriguing feature of the outcome. Most recently (2012), a report on a new study of PEG-IFN-α indicated sustained control of HIV in 9 of 20 patients who had suspended antiretroviral drugs. Intriguingly, the study also found a decrease in the latent viral reservoirs in inactive cells unreachable by by standard therapy. The interferon's mode of action was speculated to be immunomodulatory rather than directly antiviral [Montaner].

  • The jury is still out on HIV and interferon. While IFN-α has yet to find its way into mainstream clinical HIV therapy, these studies suggest a possible role, particularly in individuals early stages of HIV infection and those taking a break from standard antiretroviral drugs during Structured Treatment Interruption. A 2006 study, which found that IFN-α enhances expression of a protein (APOBEC3G) that can irreversibly inactivate the latent virus in resting CD4+ cells which form a major pool for long-term infectivity, further enhanced the possibility that interferons might eventually play a role as an early, disease-retarding drug [Chen]. Such potential use seems to complement some of what is known to date about characteristics of early and late HIV infection, as well as some of what may be true of a possible role for interferons. A feline counterpart to the human A-3G gene has not been characterized as yet and may not exist [Munk], nor is it clear that a possible A-3G protein in felines would either be upregulated by IFN-α or effectively inhibit immunodeficiency like the human protein; mouse A-3G does not show antiretroviral activity [Kobayashi]. Likewise unclear is whether the FIV VIF gene possesses mechanisms to negate a feline A-3G activity as HIV VIF does. Domestic cats do have A-3H and A-3CH genes which, in one study, reduced infectivity 5-10 fold of a VIF-deficient FIV wildtype. However, the presence of VIF protein counteracted both [Munk].

  • _____________________________________________________________________
  • References – Part 4

  • Berglund O, Engman K, Ehrnst A, Andersson J, Lidman K, Akerlund B, Sönnerborg A, Strannegård O. Combined treatment of symptomatic human immunodeficiency virus type 1 infection with native interferon-alpha and zidovudine. J Infect Dis. 1991 Apr;163(4):710-5.
  • http://www.ncbi.nlm.nih.gov/pubmed/1672701
  • Chen K, Huang J, Zhang C, Huang S, Nunnari G, Wang F, Tong X, Gao L, Nikisher K, and Zhang H. Alpha Interferon Potently Enhances the Anti-Human Immunodeficiency Virus Type 1 Activity of APOBEC3G in Resting Primary CD4 T Cells. Journal of Virology, August 2006, p. 7645-7657, Vol. 80, No. 15
  • http://jvi.asm.org/cgi/content/full/80/15/7645?view=long&pmid=16840343
  • Emilie D, et al. Early control of HIV replication in primary HIV-1 infection treated with antiretroviral drugs and pegylated IFN alpha: results from the Primoferon A (ANRS 086) Study. AIDS 15(11):1435-7, 2001.
  • http://jvi.asm.org/cgi/content/full/80/15/7645?view=long&pmid=16840343
  • Kobayashi M, Takaori-Kondo A, Shindo K, Abudu A, Fukunaga K, Uchiyama T. APOBEC3G targets specific virus species. J Virol. 2004 Aug;78(15):8238-44.
  • http://www.ncbi.nlm.nih.gov/pubmed/15254195
  • Lane HC et al. Interferon-a in Patients with Asymptomatic Human Immunodeficiency Virus (HIV) Infection. A Randomized, Placebo-Controlled Trial. Ann Intern Med. June 1, 1990 vol. 112 no. 11 805-811.
  • http://www.annals.org/content/112/11/805.abstract?ijkey=98d42a28d5f566feccf12c98aa3fb38a1fd25f35&keytype2=tf_ipsecsha
  • Montaner LJ. 19th Conference on Retroviruses and Opportunistic Infections. Seattle, Washington. 2012.
  • http://medicalxpress.com/news/2012-03-interferon-decreases-hiv-virus-antiretroviral.html
  • Münk C, Beck T, Zielonka J, Hotz-Wagenblatt A, Chareza S, Battenberg M, Thielebein J, Cichutek K, Bravo IG, O'Brien SJ, Löchelt M, Yuhki N. Functions, structure, and read-through alternative splicing of feline APOBEC3 genes. Genome Biol. 2008;9(3):R48.
  • http://www.ncbi.nlm.nih.gov/pubmed/18315870
  • Schugt I, et al. Pegylated Interferon Alpha-2b: A New Therapeutic Option in the Treatment of Early-stage HIV infection. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, 2003, abstract 59.
  • _____________________________________________________________

  • 5. Human Interferon for FIV

  • Injectable Interferon

  • No reliable research exists on injectable human interferon-alpha (HuIFN-α) as an FIV therapy. Several studies of HuIFN-α as a potential FeLV therapy established that (1) it had no ability to prevent or suppress infection unless combined with antiviral drugs such as AZT [Zeidner-Rose] and that (2) even when used alone, it did significantly reduce circulating FeLV core antigen [Zeidner-Myles]. These results, along with anecdotal accounts of use in FIV+ cats, suggested that HuIFN-α might have limited value as an FIV therapy.

  • The same study which established bioactivity against FeLV also established the fateful limitation of human interferons as feline therapeutic agents: the provoking of a neutralizing antibody response to human antigen. (It is interesting to note that significant minorities of humans who receive IFN-α also develop neutralizing antibodies, although the phenomenon occurs in the treatment of only some diseases, not others.) This response was dose-mediated and occurred in as little as three weeks at the highest dosage level attempted (1.6 x 10(6) U/kg); at lower dosage (1.6 x 10(4) to 1.6 x 10(5) U/kg) neutralization of effect was delayed until week seven. The authors of the study conclude that HuIFN-α, “at least for a limited period of time, should prove valuable in greatly reducing FeLV-FAIDS antigenic load in persistently viremic animals. In this regard, IFN-a may serve to partially restore the paralyzed immune system in these antigenemic animals, thus creating a time frame in which to reconstitute cell mediated immunity and permit a response to reduced levels of viral antigen” [Zeidner-Myles].

  • However, HuIFN-α was not without significant, if manageable, side effects. “. . . those animals that received IFN-α therapy became transiently anorexic and lost weight during the first 14 days of treatment. These symptoms dissipated by day 21, and weight gain was evident throughout the remainder of the study” [Zeidner-Myles]. The near-overlap of the cessation of side effects with the earliest date for the appearance of neutralizing antibodies does nothing to enhance the potential role of human interferon as feline therapy.

  • The authors of the FeLV study suggested the possibility that a temporary impact on FeLV at an earlier stage of infection might have lasting consequences regarding disease progression. “The importance of significant reductions in circulating antigenic load in animals with retrovirus infections is severalfold. Studies by Liu et al. suggest that a reduction in circulating FeLV antigenemia may be associated with a reversal of hypocomplementemia and a return of endogenous IFN and virus-specific neutralizing antibody production to normal levels, leading to the eventual reversal of viremia. In HIV-induced immunodeficiency disease in humans, a positive response to IFN-a treatment has been correlated with the level of pretreatment antigenemia , while progression to clinical AIDS is 20-fold greater in males who are seropositive and antigenemic. Likewise, reductions in the levels of circulating p24 induced by IFN-a have been associated with a resurgence in circulating CD4+ cells and an antitumor response to HIV-associated Kaposi sarcoma. In this regard, high levels of circulating p24 and the subsequent formation of HIV-specific circulating immune complexes have been associated with late-stage progression to clinical disease and a decline in virus-specific antibody formation in patients with AIDS. Thus, early control of retroviral antigenemia may influence subsequent immunological function and the progression to clinical disease” [Zeidner-Myles]. This hypothosis remains unproven in regard to FeLV – and by extension, FIV.

  • Low-Dose Oral Recombinant Interferon

  • Almost from the time recombinant interferons began to be used therapeutically, there has been an interest in ultra-small dosages that more closely approximate actual physiologic quantities and that avoid the problems posed by high dosages: side effects, expense, and the inconvenience of injection. It was argued that “there is virtually no physiologic circumstance in which cytokines are generated in response to a stimulus in the quantities (i.e., in the order of milligrams of protein or millions of biological units) that are required for parenteral administration. . . . Perhaps other routes, specifically oropharangeal delivery (into the nose or mouth so the cytokine reaches the oral and pharyngeal mucosa), might offer a means of engaging the cytokine network to foster beneficial effects in animals and humans” [Cummins-Krakowka]. Stomach acid neutralizes interferon when swallowed, but partisans of oral administration believed that beneficial effects could be achieved through local interactions with certain regulatory cells present in the oropharyngeal mucosa expressing interferon receptors. This interferon-cellular interaction would then be amplified into systemic effects by a cascade of cytokines (immunoregulatory proteins).

  • The identification of these regulatory cells has yet to be made, although a number of studies have purported to demonstrate local and systemic effects following oral administration of a sort that would suggest potential therapeutic benefit. Several in vivo studies of mice [Nagao] and humans [Naylor] observed changes in humoral (antibody) and cytotoxic (T cell) systems following administration. Other research has noted MHC class I antigen expression markedly increased in lymphoid cells harvested from the oropharyngeal cavity after oral administration, suggesting immune activity within local mucosal compartments [Cummins-Krakowka]. MHC class 1 expression represents activation of the so-called “complement” system, which is necessary for (among other things) effective transition from the natural to the adaptive (lymphocytic) immune response.

  • Studies of oral interferon as antiretroviral therapy have returned contradictory findings. A 1988 study of efficacy against FeLV reported that HuIFN-α given orally prevented development of fatal disease in some treated cats. However, studies in 1995 [Kociba] and 1998 [Katabira] found no beneficial effects against symptoms or disease course of FeLV and HIV respectively, and no noticeable effect on viremia or white cell counts. The only study involving FIV+ cats [Riondato, 2003] reported positive but unconvincing results. Of 25 FIV+ and FeLV+ cats in the study, 19 were FIV+. No effect on numbers of Helper T (CD4+) or Cytotoxic T (CD8+) lymphocyte subsets was noted. While FIV+ cats classified as AIDS-stage experienced no clinical benefit, benefit was claimed for symptomatic cats not classified as AIDS stage. But since antibiotic and symptomatic adjunctive therapy was also provided and since there was no control group of cats for whom it was not provided, it is not possible to conclude that the interferon therapy rather than the adjunctive therapy was responsible for clinical improvement. However, the studies are collectively representative of a point on which both partisans and skeptics generally agree. Oral recombinant interferon does not noticeably affect hematology. Benefit when and if it occurs is to clinical health.

  • A number of customary practices exist with regard to the dilution, storage, administration, and dosing of oral recombinant interferon-α. No unanimity exists on any of these practices. Dilution. 30 IU/cat is the commonly practiced dilution, although the most pointed published guidance [Weiss] cites a range from 15 - 30 IU, and one of the authors of same [Cummins, private communication] insists that 1 IU/pound is the best dose. Storage. Freezing of the dilute solution, though widely practiced by cat owners, is frowned upon by many (but not all) authorities ranging from druggists to researchers on a number of grounds: crystal formation as a result inadequate temperature control, instability of product at high dilution, etc. Administration. Since direct uptake into the bloodstream is not the prevailing model for oral interferon pharmakinetics, traditional sublingual administration at the base of the mouth beneath the tongue is not called for. Prevailing research suggests that either the gums and gum line or the anterior tongue may be the richest source of interferon receptors in the mouth. Addition of interferon to food products is an unsupported practice. Dosing. Although some vets and/or their clients practice everyday dosing of oral interferon, believing that this provides maximum therapeutic impact, Joseph Cummins, one of the pioneers and ongoing proponents of oral interferon therapy, strongly recommends adhering to a seven-days-on, seven-days-off schedule, citing over-saturation of receptors as leading to lapse in their expression [private communication].

  • Low-Dose Oral Natural Interferon (See also FIV-HealthScience “Natural Interferon Trials”)

  • An oral interferon study of FIV+ cats done in Italy and published in 2006 [Pedretti] returned a particularly attention-getting result. The study made use of a natural interferon (Alfaferone), cultured from human cell lines, rather than a recombinant interferon such as those previously described. The study involved 22 FIV+ cats, an inexplicably small control group of 5 FIV+ cats given placebo, and 3 FIV+/FeLV+ cats distributed among the two other groups. Treatment (seven-days-on, seven-days-off) was for 6 months; was followed by a two-month treatment interruption (months 6 - 8); and concluded with a second six-month period of treatment. All cats were symptomatic with some classified as AIDS-stage. According to the published report, treated cats showed a significant prolongation of survival, “dramatic” clinical improvement, in particular of fever and lymphadenopathy, but also of appetite, weight, and various internal and external immunopathologic lesions. As is generally the case with oral interferon studies, hematological and immunological parameters responded in ways that were difficult to characterize and interpret. Leukocyte numbers in treated cats showed some improvement up to month 6, a decline during treatment interruption, and a failure to regain the six-month level during the second six-month treatment period. Viral loads failed to establish a significant pattern in either treated or untreated groups. Helper T (CD4+) cells had increased mildly by month 14, Cytotoxic (CD8+) cells increased more dramatically, and CD4:CD8 ratio “worsened” during the same period. It should be noted that an increased spread between CD4+ and CD8+ cells is usual with FIV disease advancement. However, the limitations of the ratio as a benchmark of FIV immune status is well-illustrated in this study by the fact that CD4+ cells actually increased in the treated group, whereas the expected worsening of the ratio with disease progression is a function of the loss of CD4+ cells relative to their CD8+ counterparts.

  • One has to be somewhat impressed with the result of the Italian study. One of the study team indicated this reason for conducting the trial with natural rather than recombinant interferon-α. “As a matter of fact, the choice of natural versus recombinant interferon-alpha derived from previous clinical experiences in both farm animals and pets: these hinted at a better clinical benefit of natural IFN-alpha in models of both infectious and autoimmune diseases. This is not surprising: the human IFN-alpha system is highly diversified (13 genes and 5 pseudogenes). . . . As such, it can serve diverse functions, not restricted to untoward events like infection and disease. In this respect, an optimal induction of such a homeostatic control could derive from a balanced composition of different sub-units of the IFN system, with additive or synergic final effects” [Amadori, personal communication]. The number and particular subtypes of interferon-α.found in natural interferon vary with particular brand names (Alfaferone, Alferon, Multiferon, etc.). It should be pointed out that the dosage of interferon (50 IU/cat) chosen for the study was idiosyncratic to the researchers and was based on earlier success in treating equine disease. The previously mentioned guidelines for interferon dilution [Weiss] emphasize using less–considerably less–not more natural interferon as compared to recombinant interferon. “In our experience in treating cats with FeLV, . . . the optimal dose of natural HuIFN-α. is 0.5 to 2.0 IU/cat” [Weiss].

  • It is also worth noting that the use of interferon containing multiple alpha-subtypes introduces another layer of complexity into judging possible therapeutic activities that are not well understood even with one-or two-subtype products. One HIV researcher notes that “progression to AIDS is associated with elevated expression of IFN-alpha in unstimulated peripheral blood mononuclear cells. . . we sought to determine whether distinct IFN-alpha subtypes are involved in this phenomenon. Our results demonstrate that distinct IFN-alpha subtypes are sequentially activated during HIV-1 infection, which may be predictive of disease progression” [Lehmann, italics added]. So there may be good and bad alpha subtypes? An even more recent study of the anti-viral effects of IFN-α subtypes in vitro and in vivo found that subtypes α 1, α 4, α 6 or α 9 suppressed replication of a test retrovirus in vitro, but differed greatly in their anti-viral efficacy in vivo. Treatment of Friend Virus-infected mice with the IFN-subtypes α 1, α 4 or α 9, but not α 6 led to a significant reduction in viral loads. Some subtypes correlated with expansion of activated FIV-specific CD8(+) T cells and NK cells in the spleen, whereas others correlated with the activation of NK cells. “The results demonstrate the distinct anti-retroviral effects of different IFN-α subtypes” [Gerlach], and the added complexity involved in the therapeutic use of natural interferons.

  • No one is in a position to guarantee that natural interferon hinders rather than furthers FIV disease progression. Still, outcomes of the Italian study and the relatively significant period of time covered by the study are cause for hopefulness.

  • ______________________________________________________________________
  • References – Part 5

  • Cummins JM, Tompkins MB, Olsen RG, Tompkins WA, Lewis MG. Oral use of human alpha interferon in cats. J Biol Response Mod. 1988 Oct;7(5):513-23
  • http://journals.lww.com/immunotherapy-journal/Abstract/1988/10000/Oral_Use_of_Human_Alpha_Interferon_in_Cats.10.aspx
  • Cummins JM, Krakowka GS,Thompson CG. Systemic effects of interferons after oral administration in animals and humans. AJVR, Vol 66, No. 1, January 2005.
  • http://www.ncbi.nlm.nih.gov/pubmed/15691053?
  • Gerlach N, Gibbert K, Alter C, Nair S, Zelinskyy G, James CM, Dittmer U. Anti-retroviral effects of type I IFN subtypes in vivo. Eur J Immunol. 2009 Jan;39(1):136-46.
  • http://www.ncbi.nlm.nih.gov/pubmed/19130550
  • Katabira ET, Sewankambo NK, Mugerwa RD Belsey EM, Mubiru FX, Othieno C, Kataaha P, Karam M, Youle M. Lack of efficacy of low dose oral interferon alfa in symptomatic HIV-1 infection: a randomised, double blind, placebo controlled trial. Sex Transm Inf 1998;74: 265–270.
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1758122/?
  • Kociba GJ, Garg RC, Khan KNM, Reiter JA and Chatfield RC. Effects of orally administered interferon-a on the pathogenesis of feline leukaemia virus-induced erythroid aplasia. Comparative Haematology International Volume 5, Number 2 / June, 1995, 79-83
  • http://www.springerlink.com/content/h7x36v13k3l48126/
  • Lehmann C, Taubert D, Jung N, Fätkenheuer G, van Lunzen J, Hartmann P, Romerio F. Preferential upregulation of interferon-alpha subtype 2 expression in HIV-1 patients. AIDS Res Hum Retroviruses. 2009 Jun;25(6):577-81.
  • http://www.ncbi.nlm.nih.gov/pubmed/19500019
  • Nagao Y, Yamashiro K Hara N Horisawa, Kato, Katsuaki. Oral-Mucosal Administration of IFN-a Potentiates Immune Response in Mice. Journal of Interferon & Cytokine Research. September 1998, 18(9): 661-666.
  • http://www.liebertonline.com/doi/abs/10.1089/jir.1998.18.661
  • Naylor PH, Naylor CW, Hendrix S, Leveque FG. Oral Administration of Interferon-alpha Induces a Transient Decline in Oral Mucosal Immunoglobulins and an Increase in Interleukin-5. Journal of Interferon & Cytokine Research. August 1999, 19(8): 953-959.
  • http://www.liebertonline.com/doi/abs/10.1089/107999099313505
  • Pedretti E, Passeri B, Amadori M,, Isola P, DiPede P, Telera A, Vescovini R, Quintavalla F, Pistello M. Low-dose interferon-a treatment for feline immunodeficiency virus infection. Veterinary Immunology and Immunopathology 109:3-4 (2006), 245-54.
  • http://www.ncbi.nlm.nih.gov/pubmed/16169599
  • Riondato F, Gianella P, Guglielmino R, Cagnasso A, Bo S. Effects of interferon alpha (IFN-alpha) therapy on peripheral blood lymphocyte subsets from FIV and FeLV naturally infected cats. Vet Res Commun. 2003;27 1:429-32.
  • http://www.springerlink.com/content/l558w7887j488334/
  • Weiss RC, Cummins J, Richards AB. Practical Guidelines for Using low-dose orally administered huIFN-a in cats infected with FeLV, JAVMA, vol 199, No. 10, Nov 15, 1991: 1477-81
  • http://www.ncbi.nlm.nih.gov/pubmed/1666107.
  • Zeidner NS, Myles MH, Mathiason-Dubard CK, Dreitz MJ, Mullins JI, Hoover EA. Alpha Interferon (2b) in Combination with Zidovudine for the Treatment of Presymptomatic Feline Leukemia Virus- Induced Immunodeficiency Syndrome. Antimicrob Agents Chemother. 1990 September; 34(9): 1749–1756.
  • http://aac.asm.org/cgi/reprint/34/9/1749.pdf
  • Zeidner NS, Rose LM, Mathiason-DuBard CK, Myles MH, Hill DL, Mullins JI, Hoover EA.Zidovudine in combination with alpha interferon and interleukin-2 as prophylactic therapy for FeLV-induced immunodeficiency syndrome (FeLV-FAIDS). J Acquir Immune Defic Syndr. 1990;3(8):787-96.
  • http://www.ncbi.nlm.nih.gov/pubmed/2164083
  • ______________________________________________________________________

  • 6. Feline Omega Interferon for FIV

  • Injectable Interferon

  • Surprisingly little is known by first-hand study about the in vivo mode of action of feline omega interferon (FOI/IFN-ω), although it is known to bind to the same receptors as IFN-α and IFN-β. A recent study has suggested that the primary mechanism of action is probably via the innate rather than adaptive immune system [Domenech]. However, the marketer of Virbagen Omega® has freely admitted that “the exact physiological role of IFN-ω remains unknown. . . . Thus, because of the close relationship of IFN-ω with other type-1 IFNs (mainly IFN-α) and because of the now general use of IFN-α/β in human therapeutics, all available knowledge about IFN-α properties was used to assess . . . IFN-ω. . . ”[Virbagen]. The list of possible cell-associated activities is generally the same as that cited earlier for human IFN-α, and the list of possible side effects is derived directly from human experience with Type-1 interferons, although as a practical matter the Virbac FOI website (http://www.virbagenomega.com) has noted, “The only side effects that could be observed in large scale field trials were slight and transient vomiting and fatigue during the injections. These side effects were very rare and disappeared soon after the injections. No local reaction at the injection site (SC route) has ever been observed during clinical field studies. Virbagen® Omega is very safe in cats.” Transient fevers are sometimes reported during the 24 hours following an injection.

  • Large trials to date have usually established little with regard to FOI specifically as an FIV therapy. Trials involving 48, 137, and 81 cats were reported on between 2001 and 2004 [De Mari][Maynard][Mähl], and are, as might be expected, cited in Virbac promotional literature. In all cases, the decision was made to focus on cats infected with feline leukemia virus (FeLV). FIV+ cats were included only when dual infection (FeLV+/FIV+) existed. All trials required at least one clinical sign of disease for admission – Virbac is, in fact, licensed in Europe specifically for clinically symptomatic cats – and had untreated control groups. Survival rates were tracked over periods of six months to one year, and all showed higher survival rates in treated cats when compared to untreated cats. In one study, six-month survival was 2.2 times higher in treated cats. In another 26.9% of treated cats died by the one-year mark vs 38.6% of untreated cats. The third study reported generally positive effects on white cell parameters with both leukopenia (low WBC) and leukocytosis (high WBC) tending to normality by day 60 (the point at which the final series of five injections were to begin).

  • The benefits of FOI described in these studies are significant, if not always dramatic (e.g., 38.6% vs 26.9% survival). However, while FeLV is a retrovirus like FIV, the viruses do produce different diseases with different disease dynamics. (1) FeLV infects all bone-marrow precursors, whereas FIV is selectively tropic. (2) Disease progression is much more rapid and grim in FeLV+ cats once productive infection is established, a circumstance to be assumed when clinical symptoms are required for inclusion. It is not so much of a stretch as one might imagine that a given therapy could be more effective against the more devastating disease, although there is no evidence that such is the case. However, FOI activity against FeLV is still a limited basis for assuming equal or greater activity against FIV.

  • A smaller study (ten cats, five treated and five untreated) conducted in the U.K. subsequent to the French studies, involved cats experimentally infected with FIV 9 to 18 months prior to FOI therapy. “Two trials were carried out using different IFN dose regimes. The same 5 cats were treated in both trials, with the remaining 5 cats being untreated controls. Trial 1 involved treatment with subcutaneous IFN . . . for 5 days. Trial 2, started 8 weeks later, comprised daily [high-dose] oral IFN treatment . . . 6 weeks.” All cats were clinically asymptomatic at the beginning of the study and remained so at the end. Although minor (statistically insignificant) body-weight benefits were observed in treated cats, no significant improvements in viral load or CD4:CD8 lymphocyte ratio (potential benchmarks for FIV- and HIV-related immune deficits) were noted [Caney].

  • Although interesting for its demonstration of what FOI does not (at least in the short run) do, the U.K. study is essentially of utility in asymptomatic cats over periods of mere weeks, and so produces no clinically relevant information at all. For that purpose, years of treatment and observation would be required. Some of the study of human IFN-α at least raises the intriguing question of whether a protocol tailored specifically to asymptomatic cats might be fruitful. However, as Virbac notes in a Q and A section on its website, “Feline omega interferon is a cytokine, I.e. a cellular mediator presenting, in particular, antiviral and immunomodulating properties. These properties might present an interest in the treatment of cats infected with FeLV and/or FIV, in a latent stage (no clinical symptom), in order to help them to better control their infection(s). Nevertheless, no controlled double-blinded study has ever been performed to confirm the efficacy in this case.”

  • A recently published (2011) study of FeLV+ and FIV+ cats includes cats with FIV alone, some of them clinically scored for FIV-related symptoms. The sample size was relatively small (11 cats, 7 FIV+). Cats were treated for a period of 8 weeks, with assessments beginning at 2 weeks post-treatment and extending to 6 months. Overall improvement of clinical condition was characterized as "dramatic." In the initial assessment following treatment, 2 of the 3 significantly symptomatic FIV+ cats were much improved, 1 was somewhat improved. The three asymptomatic cats were still asymptomatic and remained so through all subsequent assessments. 1 mildly symptomatic cat showed no change in condition. Improvements, when they occurred, endured up to the end point of observation. Three of the cats were assessed for a full 12 months, although it is unclear which three. Significant improvements were reported in red and white cell parameters. However, in keeping with results reported in the earlier U.K. study, this one found no consistent pattern of changes in FIV-specific immune parameters such as CD4:CD8 ratio, proviral load, viremia and reverse-transcription activity. In those cats in which it initially improved, hypergammaglobulinemia (indicating heightened antibody activity) returned to baseline by the end point of observation. The general lack of improvement in FIV-specific immune parameters led the researchers to conclude that the therapeutic mechanism of the interferon was likely immunomodulatory rather than antiviral [Domenech].

  • Several one-cat field reports have cited significant benefit of FOI therapy to sick FIV+ cats. One such report was on ten-year old Poussy, a cat with no previous history of illness, who presented clinically with loss of appetite, weight loss, lethargy, dehydration, and dull coat [Vinet]. Laboratory findings were unremarkable apart from a low-normal WBC (5810/mm3) and an inverted lymphocyte:neutrophil ratio. Serum chemistries were normal. A standard 3 x 5 series of injections commencing on days 0, 14, and 60 produced a significant rise in WBC (12,780) and a normalized l:n ratio within two weeks (i.e., immediately prior to the beginning of the second series). After one month, appetite, behavior, and coat were much improved, and after two years no clinical illness had reappeared. A second report [Binaut] describes a five-year old cat with oral inflammation (“ulcerations on the tongue and discoloured oral mucosa”) and a normocytic (normal cell size), hypochromic (hemoglobin-deficient) anemia. A single five-injection series produced steady weight gain over a four-month period and a normal clinical exam, which remained unchanged at six-month and twelve-month exams. Hemoglobinemia resolved by day 14 following initiation of therapy, but returned by day 30 and was still present at day 120, although not near pre-treatment levels at either point.

  • Case histories such as these certainly suggest an FIV-specific activity in Virbagen Omega, although one has only to recall how small case studies of FOI as FIP therapy with positive outcomes later proved unrepeatable to interpret such results with caution. These studies also highlight a persistent problem in assessing the clinical impact of a disease that most often expresses itself through allowing other diseases, most of which also occur in FIV- cats, as well. In the case of Poussy, for instance, inverted lymphocyte:neutrophil ratios are seen in healthy as well as unhealthy FIV+ cats and have been known to resolve without major therapeutic intervention. Although the low-normal WBC is suggestive in light of later improvements, in this case it was clearly low neutrophils that accounted for the WBC level, and a number of things besides chronic FIV infection are able to depress neutrophil counts at a particular point in time. Was the salutary effect of FOI on the chronic FIV infection or on some transient disease state? In the second case study , there seems at least a chance that the anemic cat with oral inflammation was in the throes of a calici virus infection at the time of presentation. Calici (like herpes) commonly causes a chronic and recrudescent viral infection in FIV- as in FIV+ cats, although often more severely in the latter. The eventual return of hemoglobinemia with the passage of time after a single round of FOI is again suggestive, but given the chronicity of calici infection (quite possibly magnified by FIV-related immune deficits), it is not beyond imagining that anemia of chronic disease attaches, in part or entirely, to the calici virus rather than the FIV infection. It does no disservice to FOI as a therapeutic agent for retroviral infection to note that it has shown significant activity in independent studies as therapy for upper respiratory infection (see the “FIV and Upper Respiratory Infection” page) and gingivostomatitis (see the “FIV and Gingivostomatitis” page) associated with herpes and calici, and any pet owner will, of course, be grateful for significant improvement in health, regardless of what is being therapeutically impacted. Injection protocols can be found here. Procurement information available on request.

  • High-Dose Oral Interferon

  • By analogy to the use of low-dose human interferon-alpha, some pet owners have administered highly dilute (on the order of 30 IU per dose) feline omega interferon orally because of its convenience and long-term affordability. Virbac has not supported this practice, nor is it clear, even assuming the effectiveness of the practice, that feline interferon is markedly superior to human when the dosage is so low. A new study [Gila] of orally administered feline omega interferon for FIV+ cats has taken a somewhat different tack, substituting relatively large daily oral doses of 100,000 units (.1 MU) for the traditional low doses used in oral interferon therapy. In this study, 7 FIV+ cats used in a previous study of the SC regimen by the same research team were compared to 11 FIV+ cats treated orally. The comparison occurred over 65 days, with the oral interferon group being treated for an additional 30 days.

  • The results of the study were somewhat encouraging. Both SC and PO groups improved overall clinical scores that recorded changes in lymphatic enlargement, pathologies of the mouth and eye, faecal quality, color of mucus membranes, and changes in coat and body weight. 5 of 7 cats treated SC improved; 9 of 11 cats treated PO also improved. In both cases, improvement was noted as early as day 10. The most significant difference was that improvement in oral lesions was milder in the PO group. Within the PO group, 2 of 3 cats had mild to moderate white cell deficits normalized. 1 of 2 cats with slight anemia normalized; the other worsened. Gamma-globulins, indicative of stimulated antibody activity, increased slightly in the SC group and decreased slightly in the PO group, but the difference was not felt to be statistically significant. This group did not register increase during the study. SC treated cats did register significant gains.

  • The study team concluded that "the licensed protocol seems to be a better choice in more symptomatic cats when an effective and marked clinical improvement is desired." This conclusion was based primarily on higher levels of acute-phase proteins generated by the subcutaneous injection of the interferon. The likely reason is that injectable interferon elicits a systemic response throughout the body. The precise mode of action of oral interferon, as previously noted, has yet to be fully demonstrated. Although it has been posited that rFeIFN-ω, unlike rHuIFN-α, is resistant to stomach acid, the likeliest mode of action is stimulation of local lymphoid tissue with a secondary cascade effect on the immune system as a whole. Another reason for the team's conclusion may have been the significant improvement with SC injection in clinical scores of cats with oral disease. This may, at least in part, have stemmed from the fact that SC interferon significantly affected levels of calicivirus in a way that the the PO interferon could not. Although inflammatory oral disease has roots in a variety of chronic viral infections -- including herpesvirus and the feline immunodeficiency virus itself-- and even occurs in cats who test positive for no chronic pathogens at all, the connection of severe gingivostomatitis with chronic calicivirus infection is well documented. The oral protocol was less successful in addressing oral disease than in an earlier study of high-dose oral interferon [Hennet], the researchers speculate, because the earlier study was not limited to FIV+ cats.

  • High dose oral interferon has previously been been shown clinically effective in treatment of feline upper respiratory (see the “FIV and Upper Respiratory Infection” page) and gingivostomatitis (see the “FIV and Gingivostomatitis” page) models, but the extension to FIV+ cats as a group is a useful development. High doses of oral interferon are obviously significantly more costly than low doses, but would still prove a good deal cheaper than the SC protocol. At the .1 MU daily dosage, a single 10 MU vial of interferon would last 100 days. This study shows that beneficial immune-modulation can be obtained with oral dosing of rFeIFN-ω. Say the researchers, "Although the laboratory changes are subtler than those observed in the SC protocol, oral rFeIFN-ω nevertheless resulted in a useful improvement of the animals' condition." For this reason, the less costly and intrusive oral protocol could be a fit for the less symptomatic subset of FIV+ cats or might be a preferred choice for longer term maintenance of therapy for cats who have undergone the licensed SC protocol with some success.

  • _______________________________________________________________________
  • References – Part 6

  • Binaut P and Zoller C. A case of FIV treated with feline omega interferon Feline omega interferon was administered in monotherapy in a confirmed case of symptomatic infection with Feline Immunodeficiency Virus. Special issue of Le Point Vétérinaire, n̊ 236. June (in French) 2003.
  • Caney SMA, Helps CR, Finerty S, Tasker S, and Gruffydd-Jones TJ. Treatment of Asymptomatic Chronically FIV-Infected Cats with Recombinant Feline Interferon Omega. Proceedings of the annual conference of the American College of Veterinary Internal Medicine. June 4 to 8, 2003.
  • De Mari K, Maynard L, and Lebreux B. Therapeutic Effects of Recombinant Feline Interferon-omega on FeLV-infected and FeLV/FIV-coinfected Symptomatic Cats. J Vet Intern Med 2004;18:477-482.
  • http://www.ncbi.nlm.nih.gov/pubmed/15320583
  • Domenech A, Miro G, Collado VM, Ballesteros N, Sanjose L, Escolarb E, Martin S, Gomez-Lucia E. Use of recombinant interferon omega in feline retrovirosis: From theory to practice. Veterinary Immunology and Immunopathology 143 (2011) 301-306.
  • http://www.ncbi.nlm.nih.gov/pubmed/21719116
  • Gila S, Leala RO, McGahieb D, Sepulvedac N, Duartea A, Nizaa MMRE, Tavaresa L. Oral Recombinant Feline Interferon-Omega as an alternative immune modulation therapy in FIV positive cats: Clinical and laboratory evaluation. Res. Vet. Sci. (2013), epublished November 25.
  • http://www.sciencedirect.com/science/article/pii/S003452881300369X
  • Hennet PR, Camy G, McGahie DM, Albouy MV. Comparative efficacy of a recombinant feline interferon omega in refractory cases of calicivirus-positive cats with caudal stomatitis: a randomised, multi-centre, controlled, double-blind study in 39 cats. Jour Fel Med & Surg. 13, Issue 8, August 2011, 577-587.
  • http://www.sciencedirect.com/science/article/pii/S1098612X11001495
  • Mähl P, Maynard L, Karine De Mari K, and Lebreux B, Survival of Symptomatic FeLV or FeLV and FIV Positive Cats treated with a Recombinant Feline Omega Interferon. World Small Animal Veterinary Association Congress. Vancouver, 2004.
  • http://www.vin.com/VINDBPub/SearchPB/Proceedings/PR05000/PR00243.htm
  • Maynard L, Lebreux B, and DeMari K. Survival assessment and clinical evaluation of cats suffering from retrovirus diseases when treated with a recombinant feline omega interferon. J Interferon Cytokine Res .vol.22, Supplement 1. 2002 .
  • Vinet. C. Management of a symptomatic FIV positive cat with feline omega interferon treatment. Veterinary Interferon Handbook 2004.
  • Virbagen Omega®: The Potential of a Veterinary Interferon.
  • http://petdental.com.au/Conference%20Papers/Virbagen%20Omega.doc

  • ____________________________________________________________________

  • 7. Closing Observations

  • Injectable Human Interferon. The advent of Pegylated IFN-α, though it does nothing for the inherent limitation of high-dose therapy with human interferon in cats, at least makes it more convenient. Fewer injections are required since interferon remains in the system for a longer time. Although Peg-IFNs lower the probability of neutralizing antibody creation in humans, it is not clear that they would have a similar effect in cats. Even so, the possibility should not be dismissed that in some circumstances where feline IFN-ω is not available and might otherwise be expected to be of value, IFN-α could fill a gap, creating a time frame for temporarily reconstituting cell-mediated immunity and allowing a response to viral antigen.

  • Oral Interferon for Asymptomatic Cats. The question often arises whether low-dose oral interferon should be used prophylactically in asymptomatic FIV+ cats. Evidence derived from HIV and FIV research suggests that interferons are more efficacious earlier than later. This includes not only new infections, but asymptomatic (stage 2) infections. Although these findings do not instantly translate from high-dose injectable to low-dose oral infusion, there are suggestions in studies of oral interferon of a prima facie case for prophylactic use.

  • Recombinant vs Natural Interferon for Oral Administration. Although two studies total in FIV+ cats of recombinant and natural IFN-α are not much of a basis to generalize from, the latter appears to have performed best, and given the brevity of so many studies of therapy for FIV+ cats, even a mild increase in CD4+ cells over a 14-month period is impressive. At the level of theory it is hard to say whether the broad spectrum of alpha subtypes in natural interferon argues for or against its use, but at the level of practice, the nod seems to favor for. Certainly where sick cats are concerned, natural interferon seems more likely to produce a favorable response.

  • Feline Omega Interferon. Although there is as yet no protocol for long-term administration of feline omega interferon as a prophylactic FIV therapy, the attempt to develop such a protocol – possibly involving fewer injections at lower dosage – is overdue. The expense of the product is an unfortunate impediment to the wide adoption of such a protocol even if one could be validated. For treatment of ill cats, there is no reason not to prefer the feline interferon when it is available. While head to head studies of injectable feline vs human interferon for FIV+ cats do not appear to have been done, feline interferon has outperformed its human counterpart where other feline viruses are concerned. Recent demonstration of the clinical effectiveness of high-dose oral feline omega may prove valuable in bridging the gap between cats sufficiently immune-suppressed and clinically ill to warrant the standard injection protocol and their asymptomatic counterparts.

  • Interferons and Other Therapeutics. Most drug studies involve monotherapy for the obvious reason of preventing secondary agents from affecting results needed to validate or invalidate the effectiveness of the agent being studied. However, limited experience with interferons paired with other antiviral and immunomodulating agents indicates that those who choose interferon therapy do not need to (and probably should not) think in terms of limiting themselves to it alone out of a fear of drug interactions – or for the sake of simple expediency.

  • [Page Top]