Iron Starvation: A novel strategy for HIV and Chlamydia microbicides

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DESCRIPTION (provided by applicant): In order to control the rapid spread of HIV it is clear that multiple approaches need to be investigated. One strategy that has shown the potential to reduce transmission in non-human primates is the application of topical microbicides. In addition since it has been demonstrated that other sexually transmitted infections can also increase the transmission of HIV, microbicides that can effectively decrease the spread of other STIs may also be a strategy to decrease HIV transmission. Combinations of approaches that target different stages of the HIV and STIs developmental cycle are desirable not only from the standpoint of reducing resistance but also to attain an additive or synergistic effect. In this proposal we plan on evaluating the ability of small inhibitor molecules with a hydrazone structure to limit the infection of HIV and Chlamydia. Recently we have demonstrated that this class of compounds is able to effectively restrict the growth of Chlamydia in vitro. Furthermore the mechanism of inhibition appears to be linked to the reversible depletion of host iron stores. There is evidence that HIV development can also be modulated by host iron supplies. Therefore, development of microbicides with a common mode of action effective at limiting the growth of both HIV and Chlamydia has the potential to be a powerful weapon in the reduction of this epidemic. We initially plan to test these inhibitors using in vitro system to identify those compounds we will characterize further as to, optimum dose, cytotoxicity, stage of development affected and activity in a genital environment. Compounds that we identify that are active yet have limited cytotoxicity will be formulated as a vaginal microbicide to be tested both in a HIV hu-SCID mouse and Chlamydia mouse genital infection model. Achievement of the aims in this proposal has the potential to uncover an important weapon in the battle against HIV.