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A Mouse Model Ofaids(MAIDS) for Testing

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A Mouse Model Ofaids(MAIDS) for Testing A mouse model of AIDS(MAIDS) for testing AZT in a combination therapy with tea polyphenols. 1 2 Modiegi P. Selematsela1, 2, Rolf W. Becker , AnabeIIa Gaspax2, Zeno Apostolides I.Department of Biochemistry, University of the North, Private bag X 1106, Sovenga, 0727, South Africa 2.Department of Biochemistry, University of Pretoria, Pretoria, 0002, South Africa Summary Murine acquired immunodeficiency syndrome (MAIDS) is one of several murine AIDS models. LP­ BM5 MuLV infection of C57BL/6 mice induces a well characterized, lymphoproliferative, immunodeficiency referred to as MAIDS, which is useful for evaluation of potential antiviral agents. The MAIDS retrovirus model was used to evaluate the efficacy and toxicity of AZT and EGCg either alone or in combination. The 50% survival time for the control infected group, infected AZT treated, infected EGCg treated, and the infected group receiving AZT in combination with EGCg was 13, 15, 24, and 24 weeks respectively, while the 100% mortality results for the control infected group, AZT monotherapy, EGCg monotherapy, and AZTIEGCg combination therapy were 16, 16,31, and 33 weeks respectively. Body weight results showed that AZT monotherapy was slightly effective in preventing an increase in body weight in the infected animals while EGCg was not. The absence of toxicity and slight increase in the 50% survival time of EGCg therapy group warrant a dose response study. Key words: AZT, EGCg, CAM, MAIDS, and Combination therapy Introduction Acquired immunodeficiency syndrome (AIDS) is a clinical disorder representing the end point in a progressive sequence of immunosuppressive changes that render the body highly susceptible to tumors and opportunistic infections. The replication and pathogenesis of HN-1 has been extensively studied since it was first recognized as the agent responsible for causing AIDS. HN­ associated reverse transcriptase (HN-RT) has been considered to be one of the appropriate targets for chemotherapeutic approaches toward AIDS. The enzyme exhibits a number of features that makes it an attractive target. It is crucial for viral replication. The drug zidovudine (AZT), a synthetic thymidine analogue, has been used clinically in the management of AIDS. The drug is an effective anti-viral agent due to its ability to block HN-RT activity. Long-term suppression chemotherapy appears to improve the survival of patients with AIDS, but its toxicity renders it unsuitable for long-term chemotherapy. The major AZT-related toxicity is bone marrow suppression, which limits the dose of the drug that can be used. Adult C57BL/6 mice infected with a mixture of murine leukemia viruses show many similarities to human immunodeficiency type-l (HIV-1) infection including lymphadenopathy and splenomegally related to polyclonal activation of T and B cells to mitogenic and antigenic stimuli. Continuous administration of AZT in LP-BM5 MuLV immunodeficient virus-infected mice was found to be associated with the development of anemia, neutropenia, and thrombocytopenia similar to haematotoxicity symptoms found in humans. These problems have led to the need for alternative drugs for HIV therapy. One such alternative is to study the efficacy of combination therapy with standard anti-HN drugs and extracts from the leaves of Camellia sinensis which have been shown to have antiviral activities and are non-toxic. In studies done by Nakane et aI, the two major components of Camellia sinensis (Le., (-)-epicatechin gallate (ECg) and (-)-epigallocatechin gallate (EGCg) were found to Session m -18- differentially inhibit the activities of reverse transcriptase and cellular DNA and RNA· polymerases. EGCg has also been shown to inhibit the infectivity of influenza A and influenza B virus in Madin Darby canine kidney cells in vitro· by preventing the virus from adsorbing to these cells. We suspected that low non-toxic doses of EGCg combined with AZT would increase the efficacy of AZT monotherapy. In addition, the use of this combination therapy could be beneficial to HIV patients by reducing the toxicity and cost of AZT monotherapy. The aim of this study was therefore to investigate whether AZT and EGCg when used in combination would improve survival of the animals infected with LP-BM5 MuLV. Materials and Methods Zidovudine capsules (containing >90% AZT) for treating the animals were purchased from a local pharmacy. Polyphenon E was a gift from Dr. Y. Hara (Mitsui Norin Corporation, Japan). Polyphenon E comprises of (+)-Gallocatechin (1.4 %), (-)-Epigallocatechin (17.6%), (-)-epicatechin (5.8%), (-)-EGCg (53.9%), (-)-epicatechin gallate (12.5) and caffeine (0.5%). Female 5-7 weeks old C57BL/6 mice were purchased from the University of Cape Town Medical School, Animal Unit. Animals were housed in microisolator cages in humidity and temperature controlled environment and were fed with standard mice chow and water ad libitum. The mice were housed in the animal facilities of the Medical Research Council (MRC) of South Mrica in Pretoria. Cages, bedding, and food were autoclaved prior to use and all cage changes and animal handling were performed in laminar airflow hoods to protect the animals from opportunistic infections. Ventilation and airflow in the animal facility was set to twelve changes per hour. Room temperature was regulated at 20°C and the rooms were set on automatic twelve-hour light and dark cycles with the light period beginning at 6:00 am. The experimental protocol was approved by University of Pretoria ethical committee for animal studies. The animals were assigned to the 8 groups as shown in Table 1 by using the PLAN procedure of the SAS software package. The LP-BM5 cell line was a gift from Prof. Vince Gallicchio, University of Kentucky. This LP-BM5 stock was kept at -70°C until used. The LP-BM5 cells were grown to approximately 90­ 95% confluency in three or four days without changing the media. Mter 13 passages, the supernatant from each flask was decanted and all the cellular debris were removed by centrifugation at 2000 rpm for 10 minutes and then passed through 0.45 micron Millipore filters. The cell free, 0.45 micron filtered LP-BM5 cell supernatant was then administered to mice by in~aperitoneal injection of 0.4 mI. The effectiveness of AZT and EGCg therapy alone or in combination, as antiretroviral treatment in LP-BM5MuLV infected mice was measured by following the survival of the animals for up to 34 weeks and by measuring body weights of the animals from the beginning of the experiment until week 21. AZT and EGCg either alone or in combination were administered in the drinking .water at a concentration of 0.25 mg/ml and 1.0 mglml respectively for the duration of the experiment, beginning twenty-four hours after inoculation. This is equivalent to approximately 50 mg/kg/day AZT and 200 mglkg/day EGCg. This AZT dose is normally used in the MAIDS model. The dose of tea normally used in animal experiments is 1% (w/v) tea and varies from 0.5 ­ 2.0 (%w/v) tea in water. Tea normally contains 33% soluble solids, of which EGCg is about 10%, thus at the normal dose the animals receive about 0.033% (w/v) EGCg. The Imglrrll dose used here is 0.0584% (w/v) EGCg. Three animals were sacrificed from each group at week 16 post inoculation. Survival was monitored daily and the experiment was terminated after 33 weeks. Results and Discussion All the uninfected animals were still alive when the experiment was terminated at week 33, indicating no adverse effect from single or combination therapy. No statistically significant -19- Session m differences were detected on weight gain of animals in all uninfected groups. The infected animals (Group 5) began dying at week 12 P.I. The last animal was sacrificed in week 16. EGCg monotherapy (Group 7) had three animals surviving in week 16. These were also sacrificed for histological evaluation. AZT monotherapy (Group 6) on the other hand increased survival time of the animals by 16 weeks (100% mortality at week 31). Combination therapy (Group 8) increased survival time of the ~imals by up to 18 weeks (100% mortality in week 33). The slight improvement in the 50% survival time for the EGCg group and the 100% mortality time for the combination therapy cannot be analysed statistically due to the small number of the animals. There is no explanation for the early deaths in the infected animals receiving combination therapy (Group 8) at this stage. Conclusion From this study, it can be concluded that AZT therapy prolonged survival of animals when therapy was initiated 24 hours after virus inoculation but did not eradicate the virus. EGCg at the dose used showed a slight improvement on the survival of infected animals as compared to the infected animals without any treatment. Both AZT and EGCg either as single agents or in combination did not show any toxicity as all uninfected animals receiving treatments were still well and alive at termination. Further studies are required to optimize the doses of AZT and EGCg in the combination therapy. Table 1. Survival of the infected and uninfected C57BL/6 female mice for single or combination therapy. Animals were treated as described in materials and methods with 0.25 mglml AZT andlor 1 mglml Polyphenon E in drinking water. Mice Group Therapy 50% survival 100% mortality number time in weeks time in weeks Uninfected 1 Control >33 >33 2 AZT >33 >33 3 EGCg >33 >33 4 AZT+EGCg >33 >33 Infected 5 Control 13 15 6 AZT 24 31 7 EGCg 15 16 8 AZT+EGCg 24 33 Session ill -20- SUlVival ofC57BU6 female mice ____uninf(l) -+-uninf+ A (2) 100 ·-f ]{ ] ]]]{]{] J J] • --.. ~ -_.- -.-- --- -- ---- - ~ uninf + E (3) -+--t-'~- --.-uDinf + A + E (4) 90 -.-- -- _.- - _. --1--,-- --- -- I--I-'.---t-- \- -..... --- >-+- ----- - - - - . ........inf(5) 80 -- _.- - ~inf+A(6) 70 - _._-- -...inf+E(7) -0-inf + A + E(8) 30 -_.
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