The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.
The development of therapeutic agents for use in human HIV infection and AIDS has been painfully slow. Several years after the introduction of the drug azidothymidine (AZT), it remains the best drug available. However, at this time, there is a backlog of some 60 drugs which are waiting for clinical testing. Clearly, an animal model which might prove useful as a prescreen for clinical trials would provide a useful tool in setting priorities. But in addition, with many community based trials of a wide variety of compounds currently ongoing, it seems that there is at least a possibility that some of these drugs may actually enhance the course of the AIDS progression. An animal model, then, could be useful on at least two fronts: as a, prescreen for therapeutically useful compounds and in an immunotoxicological mode to predict negative therapeutic outcomes. It is in this context that the studies of the effect of dideoxyadenosine (DDA) on the progression of MAIDS should be viewed. LP-BM5 is the name given to a mixture of two murine leukemia viruses (MuLV) which have been grown in a bone marrow cell line. These MuLV were originally isolated by Laterjet and Duplan and are somewhat unusual because they induce nonthymic lymphomas (as opposed to thymic lymphomas) and theyare able to infect adult mice. The mixture was originally thought to induce reticulumcell neoplasms in susceptible mice and, thus, was given the designation RCN-BM5. The name LP(lymphoproliferative)-BM5 has been proposed for these MuLV in response to evidence that the proliferation of B cells observed after virus inoculation was polyclonal and not truly neoplastic in nature. However, the most recent report from this group indicates that although the B cell proliferation early in the course of infection is polyclonal, late in the infection oligoclonal B cell proliferation is observed.Additionally, the ability to develop continuous cultures of cells from these mice (B and pre-B cells) indicates that some of the cells have been transformed. The fact that the viruses in the mixture are retroviruses and induce an immunosuppression with many similarities to the human disease AIDS has lead Morse and co-workers to refer to the LP-BM5-induced immunopathology as MAIDS (murine acquired immunodeficiency syndrome).
The objective of these studies was to determine how the drug DDA would impact immune systems of mice infected with the immunosuppressive retrovirus LP-BM5 (MAIDS). The studies were designed to determine if the drug would either accelerate or inhibit the disease-induced immune pathology. Doses of DDA ranged from those which were well tolerated to those in which overt immunotoxicity was observed.
Table 1 summarizes the data from the standard toxicology studies. Body weights were not found to be altered in any of the groups. However, MAIDS viral infection induced a dramatic increase in weight of the spleens of the infected animals. The spleen weights in animals treated with DDA was not significantly different from the vehicle-treated group in either the MAIDS-infected or uninfected mice and, thus, there is no evidence that DDA treatment was able to ameliorate the disease process.
The data in Table 2 is a summary of the immunology studies. A decrease in the relative number of splenic Thy 1.2+ and Lyt2+ cells was observed. The specific IgM response to the T-dependent antigen sRBC was greatly reduced (~90%) in DDA-treated mice. Additionally, the specific IgM response to sRBC was eliminated (99%) in the MAIDS-infected mice. This humoral immunosuppression was neither improved nor worsened by DDA treatment. At the same time as the specific humoral response was observed to decrease, a large increase in total serum IgM was observed. Once again, this effect was not altered by treatment with DDA. Both NK and CTL activity were increased in MAIDS-infected mice and both remained untouched by DDA treatment.
The data gathered in these studies do not provide any evidence of the ability of the dideoxynucleotide DDA to alter the course of disease progression in MAIDS-infected mice. DDA did not slow the course of MAIDS infection but, on the other hand, it did not accelerate the course of the disease, even at immunotoxic doses.