HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 POL GENE-MUTATIONS IN AN AIDS PATIENT TREATED WITH MULTIPLE ANTIRETROVIRAL DRUGS

Multiple mutations were found in the human immunodeficiency virus pol gene following treatment of an AIDS patient with antiretroviral drugs. After approximately 2.5 years of monthly alternating therapy with 3'- azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), most of the pol sequences amplified from the patient's peripheral blood monon uclear cell DNA contained known AZT resistance mutations at codons 41, 67, and 215 and a putative ddC resistance mutation at codon 69 as wel l as other novel mutations. These mutations persisted for 6 months aft er the patient was switched to 2',3'-dideoxyinosine monotherapy. Mutat ions known to be associated with 2',3'-dideoxyinosine resistance did n ot occur during this time. Antiviral susceptibility testing of point m utants, introduced into the genetic background of laboratory strain NL 4-3, showed that the codon 41 mutation antagonized ddC resistance when present with the codon 69 mutation. However, this antagonism was not found with a chimeric mutant containing the patient's pol gene sequenc e from codons 25 to 218, implying that other mutations compensated for the antagonism. Thus, alternating therapy with AZT and ddC resulted i n the selection of viruses resistant to both drugs.