Curcumin and FIV
Click here to open a Glossary of Terms in a separate window.
Curcuminoids are the primary content of the culinary spice turmeric. There is no research relating directly to curcumin as an FIV therapy, but there is an abundance of research with regard to HIV. The total picture presented by this research is checkered. Curcumin may or may not be an indicated supplement for someone with HIV (and by extension FIV), although the balance of evidence is progressively tilting toward the positive.
On the one hand, it has recently demonstrated the ability to reduce HIV p24 core antigen in chronically infected CD4+ cell lines [Riva]. CD4+ lymphocytes are the primary target of HIV and FIV. In vitro experiments have established that curcumin inhibits protease and integrase, two enzymes required for viral replication [Mazumder]. It can also inhibit replication of HIV by inhibiting transcription signalling of the viral long terminal repeat, the end-gene that functions as an on-off switch [Li]. Curcumin binds and activates a receptor (PPAR-γ) on dendritic cells which inhibits their ability to capture HIV and unwittingly transfer infection to T-cells [Jacob]. Curcumin also down-regulates AP-1 transcription factor, which is known to be one of the major host factors coopted by FIV to boost viral replication [Ishikawa]. And curcumin down-regulates human CXCR4 [Skommer], which is nearly (94.9%) identical to feline CXCR4 and which is the primary co-receptor on the cell surface used (along with the CD134 molecule to which the virus initially binds) to infect cells. Curcumin has strong anti-inflammatory qualities through suppression of inflammatory signaling proteins (“cytokines”) TNF-α, Interleuken (IL)-1β, and IL-6.
On the more questionable side of the ledger, curcumin’s anti-inflammatory activity also inhibits synthesis of IL-2 (necessary to activation and expansion of CD4+ T cells), suppresses IL-12 ( a co-stimulatory molecule, along with IL-2, necessary to CD8+ cell activation), and upregulates IL-4 and IL-10, both inducing antibody, not T cell immune response [Kang]. Although other other anti-inflammatory suppressors of IL-2 and IL-12 have shown therapeutic value through in vivo studies, no in vivo studies have clearly validated the therapeutic benefit of this activity by curcumin. And on the obverse side of its ability to reduce HIV p24 in CD4+ lymphocytes, it actually increases it in latently infected promonocytic (i.e., premacrophagic) cell lines [Barquero]. HIV and FIV, it should be remembered, infect both lymphocyte and macrophage cell lineages, although the latter has no direct significance for the degradation of immunity. The point has been made that inducing viral expression in latently (inactively) infected cells might actually be a good thing, since this exposes the otherwise unreachable reservoir of infection to the immune response and/or to other antiviral agents concurrently being given. This is purely conjecture, though. Questions, therefore, linger regarding curcumin’s possible antiretroviral benefit, although the preponderance of evidence points in that direction.
In 1994, Search Alliance, a Los Angeles community based research group, reported the results of their 20-week pilot study in which curcumin (2.6 grams per day) “was able to produce a mild antiviral effect in terms of reduction of viral load as measured by RNA PCR in all 11 of the 19
participants who completed the study. . . although no increase in CD4 cells were reported” [Hale]. Several years later, a New England clinical trial involving HIV patients “examined curcumin and its effectiveness as an antiviral agent in 40 participants. Viral load tests, including
baseline testing, were conducted in the fourth and eighth weeks, following high- and low-dose regimens. The study found no evidence that curcumin reduced viral load or increased CD4 counts. Despite this finding, patients claimed they liked taking curcumin because they felt better and were willing to put up with the minor gastrointestinal effects” [James]. This result should not be surprising, however, because curcumin suffers from a defect that adversely impacts almost every therapeutic use in which systemic rather than local action is required: it is largely water-insoluble and has poor bioavailability: it isn't taken up well in the intestine, it achieves poor serum levels in the blood, and it is metabolized and exits the system rapidly. This is not so much of a problem in treatment of skin lesions, gingivostomatitis or bowel disease, where curcumin comes in direct contact with inflamed or infected tissue. Systemic diseases are another matter entirely.
The unresolved issue of curcumin’s suitability as antiretroviral therapy is made all the more vexing by the fact that human and animal studies have established curcumin’s usefulness in treating inflammatory diseases, many of which are secondary complications of FIV. These include
pancreatitis [Durgaprasad], colitis & inflammatory bowel disease [Holt], retroviral associated
diarrhea [Conteas], hepatitis, jaundice, diabetes, and bacterial infections [Itokawa]. Anecdotal success in treating feline gingivostomatitis has also been reported. This anti-inflammatory activity is accomplished through curcumin’s ability to affect “the metabolism of arachidonic acid, activities of cyclooxygenase, lipoxygenase, cytokines (interleukins and tumor necrosis factor), nuclear factor-kB (NF-κB) and release of steroids” [Itokawa]. There is also an accumulating mountain of data on curcumin’s promise in treating a variety of cancers, including lymphoma, the most frequent fatal feline cancer. “Curcumin has been shown to have cancer chemopreventive potential against a variety of tumors via targeting key survival pathways that are aberrantly activated in cancer cells. . . . curcumin hardwires to multiple cellular processes. Suppression of cell proliferation, induction of apoptosis, and inhibition of metastasis are
considered to be the major mechanisms underlying its anticancer properties” [Uddin].
For improved systemic benefit, formulation of curcumin with substances designed to boost bioavailability is highly desirable. This has been accomplished in several ways, but cross comparisons are difficult because the studies that underlie various strategies differ in design. The key points to pay attention to are serum levels achieved in the blood and length of time the levels are maintained. Additional considerations are in vivo levels of individual curcuminoids -- most notably, curcumin, demethoxycurcumin, bisdemethoxycurcumin, and the metabolite tetrahydrocurcumin -- with varying individual concentrations seeming to produce optimal effects in different disease situations. Although the metabolite possesses the highest antioxidant capacity, total capacity also decreases with a decrease in the number of methoxy groups [Jäger]. There are numerous boosted curcumin products already on the market, and a number of others in the pipeline.
One method of boosting curcumin bioavailability is the combining of curcumin with the piper nigrum extract piperine (marketed as Bioperine), which enhances uptake in the intestine and inhibits degradation ("glucuronidation") in the liver. In one study in humans "after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects" [Shoba]. Several brands of curcumin supplements are commercially available in which the curcumin is mixed with piperine.
Alternative routes to boosting bioavailability (and antioxidant capacity) are through lipidation, micellization, or hydrophilizing of the curcumin by trade-marked processes. Increases in peak serum concentration and sustained retention time tend to vary from study to study, but each process registers significant increases in both areas and exceeds piperine-boosting considerably in the latter. One process, marketed as Meriva, uses curcumin-phosphatidylcholine complexes and has been validated by several trials [Maiti][Marczylo]. (One manufacturer offers a time-release formulation of Meriva.) Longvida is another entrant to the field demonstrating enhanced bioavailability [Gota]. Its formulation is described as a "solid lipid curcumin particle (SLCP)" complex. A third approach, trademarked as Biocurcumax (BCM 95™), involves dissolving standardized curcuminoids in an essential oil of turmeric [Benny]. Curcumin so dissolved can then be directly absorbed into the lymphatic system,
bypassing the liver (the so-called "first-pass phenomenon"). Curcu-Gel uses a trademarked "softsule®" delivery of BCM 95 and cites a trial showing improved bioavailability [Mukkadan]. Thorne has recently introduced a lipid formulation intended for animals called CurcuVet. Citation of research by Thorne seems to indicate that the product is based on the Meriva formulation. A Swiss-German product, NovaSol Curcumin, engineers curcumin into micelles (colloidal particles) [Schiborr], and a recently released product, CurcuWin, uses the hydrophilic carrier polyvinylpyrrolidone to enhance solubility [Jäger]. For those using products intended for humans, powders may prove easier to downsize to a desired feline dosage.
Among the promising and exciting developments has been the expanding research into encapsulation of curcumin in tiny nanoparticles as vehicles for uptake and intracellular transport. Studies have demonstrated that the unique size range and solubilizing properties of such nanoparticles increase bioavailability and enhance activity against a variety of bacterial and fungal pathogens. The curcuminoids are dissolved into a lipid during the process of encasement in phospholipid shells called solid lipid nanospheres, or SLNs. A recent HIV study used apotransferrin, a glycoprotein related to lactoferrin, to carry curcumin into HIV-infected cell lines via the cells' transferrin receptors. Researchers found that curcumin so delivered had magnified anti-inflammatory action and inhibited HIV at the integration (into cellular DNA) stage in a way that the same curcumin not encased in nanoparticles did not [Gandapu]. [Wang].
Curcumin is a safe supplement for cats. Toxic limits have been set very high in animal studies,
and although ulcerogenic dosages in a study of rats were set at 100 mg/kg [Prasad], one private pet owner, whose cat suffered from myelofibrosis, has reported via his website daily dosages as high as 1 to 1 1/2 gms of unenhanced curcumin and 500 mgs of both piperine-enhanced curcumin and Curcu-Gel without side effects. While there is no information to suggest what an FIV-specific dosage might be, one veterinary source has suggested c.70 mg twice daily for control of stomatitis [Rochette]. Boosted formulations generally contain less curcumin per unit volume to accommodate the carrier, so more mg/kg are possible, although practical limitations relating to administering to a cat must be taken into account. Because it induces bile flow, curcumin should not be given to cats with impaired bile duct clearance. Long-term administration at high dosage could conceivably deplete iron. Reports are that curcumin/turmeric is mild enough in taste that some cats willingly eat food to which it has been added. It does stain, however, so administration to vomiting cats may cause problems for the owner.
Barquero AA, Davola ME, Riva DA, Mersich SE, and Alche LE. Naturally Occurring Compounds Elicit HIV-1 Replication in Chronically Infected Promonocytic Cells. Biomed Res Int., Published online 2014 May 12.
Benny M et al. Bioavailability of Biocurcumax (BCM-095TM). Research & Development Laboratory, Arjuna Natural Extracts Ltd., 2006.
Conteas CN, Panossian AM, Tran TT, Singh HM. Treatment of HIV-Associated Diarrhea with Curcumin. Dig Dis Sci. 2008 Dec 3.
Durgaprasad S, Pai CG, Vasanthkumar, Alvres JF, Namitha S. A pilot study of the antioxidant effect of curcumin in tropical pancreatitis. Indian J Med Res. 2005 Oct;122(4):315-8.
Gandapu U, Chaitanya RK,Kishore G,Reddy RC, and Kondapi AK. Curcumin-Loaded Apotransferrin Nanoparticles Provide Efficient Cellular Uptake and Effectively Inhibit HIV-1 Replication In Vitro. PLoS One. 2011; 6(8).
Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG.. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem. 2010 Feb 24;58(4):2095-9.
Hale P. Curcumin Study Validates Strategy of Pursuing Other LTR Inhibitors. 1994.
Holt PR, Katz S and Kirshoff R. Curcumin Therapy in Inflammatory Bowel Disease: A Pilot Study. Digestive Diseases and Sciences Volume 50, Number 11 / November, 2005: 2191-2193.
Ishikawa Y, Yokoo T, Kitamura M. c-Jun/AP-1, but not NF-kappa B, is a mediator for oxidant-initiated apoptosis in glomerular mesangial cells. Biochem Biophys Res Commun. 1997
Itokawa H, Shi Q, Akiyama T, Morris-Natschke SL, and Lee K-H. Recent advances in the investigation of curcuminoids. Chin Med. 2008; 3: 11.
Jacob A, Wu R, Zhou M, Wang, P. Mechanism of the anti-inflammatory effect of curcumin: PPAR-[gamma] activation. Highbeam Research (January 1, 2007).
Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpural M, Wilson, JM. Comparative absorption of curcumin formulations.
Nutrition Journal 2014, 13:11.
James JS. Curcumin: clinical trial finds no antiviral effect. AIDS Treat News. 1996 Mar 1;(no
Kang BY, Song YJ, Kim K-M ,Choe YK, Hwang SY and Kim TS. Curcumin inhibits Th1
cytokine profile in CD4+ T cells by suppressing interleukin-12 production in macrophages.
British Journal of Pharmacology (1999) 128, 380-384.
Li CJ, Zhang LJ, Dezube BJ, Crumpacker CS, and Pardee AB. Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication.
Proc Natl Acad Sci U S A. 1993 March 1; 90(5): 1839-1842.
Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin-phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm. 2007; 330 (1-2): 155-163.
Marczylo TH , Verschoyle RD, Cooke DN, Morazzoni P, Steward WP and Gescher AJ.
Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemotherapy and Pharmacology. Volume 60, Number 2 / July, 2007: 171-177.
Mazumder A, Wang S, Neamati N, Nicklaus M, Sunder S, Chen J, Milne GW, Rice WG, Burke TR Jr, Pommier Y. Antiretroviral agents as inhibitors of both human immunodeficiency virus
type 1 integrase and protease. J Med Chem. 1996 Jun 21;39(13):2472-81.
Mukkadan JK. Bioavailability of Curcu-Gel Softsules. Little Flower Medical Research Center. no date.
Prasad, DN, Gupta, B, Srivasta, RK, Satyavati, GV. Studies on ulcerogenic activity of curcumin. Indian J. Physiol.Parmacol. 1976, 20, 92.
Ranjan D, Johnston DT, Wu G, Elliott L, Bondada S, Nagabhushan M. Curcumin blocks
cyclosporine A-resistant CD28 costimulatory pathway of human T-cell proliferation. J Surg Res
(1998) 77: 174-8.
Riva DA, Fernandez-Larrosa PN, Dolcini GL, Martinez-Peralta LA, Coulombie FC, Mersich SE.. Two immunomodulators, curcumin and sulfasalazine, enhance IDV antiretroviral activity in HIV-1 persistently infected cells. Arch Virol. 2008;153(3):561-5. Epub 2008 Jan 4.
Rochette J. Feline Stomatitis. 2005. wvc.omnibooksonline.com/data/papers/2005_V125.pdf
Schiborr C, Kocher A, Frank J. Oral bioavailability of curcumin from a micronized powder and micelles is 9- respectively 200-fold higher than that of native curcumin in healthy young women and men. Free Radical Biology and Medicine. 2013; 65, Supplement 1, s49.
Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998
Skommer J, Wlodkowic D, Pelkonen J. Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp. Hematol. (2007).
Uddin S, Khan AS, Al-Kuraya KS. Developing curcumin into a viable therapeutic for lymphoma. Expert Opin Investig Drugs. 2009 Jan;18(1):57-67.
Wang Y, Lu Z, Wu H, Lv F. Study on the antibiotic activity of microcapsule curcumin against foodborne pathogens. Int J Food Microbiol. 2009 Nov 30;136(1):71-4.