ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS-1 (HIV-1) ACTIVITIES OF 3-DEAZAADENOSINE ANALOGS - INCREASED POTENCY AGAINST 3'-AZIDO-3'-DEOXYTHYMIDINE-RESISTANT HIV-1 STRAINS

3-Deazaadenosine (DZA), 3-deaza-(+/-)aristeromycin (DZAri), and 3-deaz aneplanocin A (DZNep) are powerful modulators of cellular processes. W hen tested against H9 cells infected acutely with two different strain s of human immunodeficiency virus 1 (HIV-1) and in the chronically inf ected monocytoid cell lines U1 and THP-1, the 3-deazanucleosides cause d a marked reduction in p24 antigen production. Similar reductions in p24 antigen were seen in phytohemagglutinin-stimulated peripheral bloo d mononuclear cells infected with clinical HIV-1 isolates. Strikingly, in comparing the therapeutic indices between the paired pre- and post -3'-azido-3'-deoxythymidine (AZT) treatment HIV-1 isolates, DZNep and neplanocin A showed an increase of 3- to 18-fold in their potency agai nst AZT-resistant HIV-1 isolates. In H9 cells treated with DZNep and D ZAri, the formation of triphosphate nucleotides of DZNep and DZAri was observed. The mode of action of DZNep and DZAri appears complex, at l east in part, at the level of infectivity as shown by decreases in syn cytia formation in HIV-1-infected H9 cells and at the level of transcr iption as both drugs inhibited the expression of basal or tat-induced HIV-1 long terminal repeat chloramphenicol acetyltransferase activity in stably transfected cell lines. Since DZNep induced in H9 cells a ra pid expression of nuclear binding factors that recognize the AP-1 tran scription site, the anti-HIV-1 activity of the DZA analogs could partl y be the induction of critical factors in the host cells. Thus, the 3- deazanucleoside drugs belong to an unusual class of anti-HIV-1 drugs, which may have therapeutic potential, in particular against AZT-resist ant strains.