Over 1,000,000 Americans and 15 million individuals worldwide are infected with HlV. These numbers have been projected to be in the range of 40 - 100 million by the year 2000. Chemotherapeutic suppression of viral replication provides the greatest likelihood of beneficial intervention in the natural history of disease progression, at least for the near future. Three nucleoside analogs (zidovudine [AZT], dideoxyinosine [ddI], and dideoxycytosine [ddC]) have been approved for use in the United States. In certain patient populations these can prolong life and reduce morbidity; nevertheless, much room for improvement remains. In addition, herpesviruses (HSV, VZV, and CMV) represent the most prevalent and significant opportunistic viral complications of HIV disease. The identification of effective drug regimens for both HIV and the herpesviruses must contend with a number of hurdles. One of the most important of these is drug resistance. The objectives of this proposal are to characterize the expression, the genetic basis, the mechanisms, and approaches to treat antiviral drug resistance.
Specific aims i nclude 1) the investigation of the nature and significance of nucleoside drug resistance, 2) the confirmation or denial of the hypothesis that higher plasma levels of non-nucleoside reverse transcriptase inhibitors can effectively suppress drug resistant virus, 3) the determination whether the clinical failure of the tat antagonist Ro 24-7429 is attributable to TNFalpha and whether inhibitors of TNFalpha can synergize tat antagonist activity, 4) to examine drug resistance with protease inhibitors, 5) to determine whether HIV gene therapies, like antisense oligonucleotides and ribozymes, can select for escape mutants (resistance), and 6) to develop compounds that effectively bypass drug resistance caused by acquired or innate kinase deficiencies of herpesviruses like HSV and CMV. These studies involving both specimens from clinical investigations and more basic molecular biologic and biochemical approaches are intended to elucidate new approaches to treat HIV and opportunistic herpesvirus infections more effectively.
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