REVERSE TRANSCRIPTION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IS BLOCKED BY RETROVIRAL ZINC-FINGER INHIBITORS

The Cys-Xaa(2)-Cys-Xaa(4)-His-Xaa(4)-Cys zinc fingers of retroviral nu cleocapsid (NC) proteins are prime antiviral targets due to conservati on of the Cys and His chelating residues and the absolute requirement of these fingers in both early and late phases of retroviral replicati on. Certain 2,2'-dithiobisbenzamides (DIBAs) chemically modify the Cys residues of the fingers, thereby inhibiting in vitro replication of h uman immunodeficiency virus type 1 (HIV-1). We examined the consequenc es of DIBA interaction with cell-free virions and their subsequent abi lity to initiate new rounds of infection. The DIBAs entered intact vir ions and chemically modified the p7NC proteins, resulting in extensive disulphide cross-linkage among zinc fingers of adjacent p7NC molecule s. likewise, treatment of Pr55(gag)-laden pseudovirions, used as a mod el of virion particles, with DIBAs resulted in Pr55(gag) cross-linkage . In contrast, monomeric p7NC protein did not form cross-linkages afte r DIBA treatment indicating that the retroviral zinc Finger proteins m ust exist in close proximity For cross-linkage to occur Cross-linkage of p7NC in virions correlated with loss of infectivity and decreased p roviral DNA synthesis during acute infection, even though DIBAs did no t inhibit virus attachment to host cells or reverse transcriptase enzy matic activity. Thus, DIBA-type molecules impair the ability of HIV-1 virions to initiate reverse transcription through their action an the retroviral zinc finger, thereby blocking further rounds of replication .