SYNERGISTIC DRUG-INTERACTIONS OF AN HIV-1 PROTEASE INHIBITOR WITH AZTIN DIFFERENT IN-VITRO MODELS OF HIV-1 INFECTION

Synthetic peptide mimetic inhibitors of HIV-1 protease effectively blo ck spread of infectious virus in acutely infected T-cells. These compo unds also inhibit production of infectious virions from chronically in fected T-cell lines. In order to determine the potential for drug inte raction effects on antiviral activity, an HIV-1 protease inhibitor (SK &F 108922) and AZT were studied in three different in vitro models of HIV-1 infection of T-cell lines, specifically, (1) acutely infected ce lls infected at low multiplicity, (2) HIV-1 chronically-infected cells and (3) co-cultivations of chronically infected with non-infected cel ls. Upon co-treatment, these compounds demonstrated synergy in Molt4 o r H9 cells acutely infected with HIV-1 strain III(B). Either compound alone was a potent inhibitor of HIV-1 in co-cultivations of uninfected and chronically infected cells. In combination treatments of co-cultu res, SK&F 108922 demonstrated strong synergy with AZT. Treatment of H9 /III(B) chronically infected cells demonstrated no inhibitory effect b y AZT treatment (EC50 = > 100 muM) whereas SK&F 108922 was inhibitory (EC50 = 3 muM). Upon co-treatment of H9/III(B) chronically infected cu ltures with both compounds, the antiviral activity was similar to that of the protease inhibitor alone suggesting no drug interaction. In th e co-cultivation experiments, AZT's antiviral effect was most likely d ue to blocking spread of acute infection to uninfected cells in the cu lture. No antagonistic effects were observed with AZT and SK&F 108922 co-treatments. These results clearly demonstrate that an HIV-1 proteas e inhibitor can exert a potent antiviral effect on chronically infecte d T-cells in contrast to AZT and is capable of potent synergy with AZT in acute and co-culture in vitro infection models.