MECHANISM OF IMMUNOTOXICITY OF THE AIDS THERAPEUTICS DDC AND D4T

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The 2',3'-dideoxynucleosides are the only approved therapeutics for slowing of the progression of the human immunodeficiency virus (HIV) which is known to cause acquired immunodeficiency syndrome (AIDS). There is mounting evidence that these analogs of endogenous precursors for DNA replication are potentially toxic towards several organs. Previous studies in this laboratory have indicated that CD4+ lymphoid cells significantly decreased in the circulating pool of lymphocytes in the nonhuman primate species, rhesus monkey. The goal of this proposed research is to elucidate the mechanism of toxicity of the nucleoside analogs, ddI and d4T towards the immune system at the cellular level. Our hypothesis is that nucleosides cause a delayed cytotoxicity in specific lymphocyte subpopulations, namely CD4+ helper T cells. It is known that dideoxynucleosides disrupt normal mitochondrial biogenesis and we propose that toxicity is mediated by dysfunction of the mitochondria in proliferating lymphocytes. A deficit in mitochondrial activity could result in a lowering of ATP and the enhancement of cell death or turnover of lymphocytes. This scenario could be one explanation for the observed decrease of CD4+ cells we observed in previous experiments in nonhuman primates that were exposed to ddC and ddI. To accomplish the goal, we first propose to measure shifts or changes in the number of lymphocytes expressing the CD4 surface marker in normal and beta2-microglobulin gene inactivated, transgenic mice. We will observe the direct effect of nucleosides on CD4+ cells in these transgenic animals. Secondly, we propose to characterize any changes in the immune responsiveness of lymphocytes which may be induced by nucleoside exposure. Finally, we propose to assess the effect of in vivo exposure to ddC and d4T on the functional capacity of lymphoid cell mitochondria by measuring the effect on the mitochondrial specific enzyme cytochrome oxidase. We feel these approaches will elicit important information which can be applied to the administration of these drugs in HIV seropositive and AIDS patients.