INACTIVATION OF MURINE LEUKEMIA-VIRUS BY COMPOUNDS THAT REACT WITH THE ZINC-FINGER IN THE VIRAL NUCLEOCAPSID PROTEIN

All retroviral nucleocapsid (NC) proteins, except those of spumaretrov iruses, contain one or two copies of the conserved sequence motif C-X( 2)-C-X(4)-H-X(4)-C. The conserved cysteine and histidine residues coor dinate a zinc ion in each such motif, Rice et al. (W. G. Rice, J. G. S upko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. O. Arthur, and L. E. He nderson, Science 270:1194-1197, 1995) have described a series of compo unds which inactivate human immunodeficiency virus type 1 (HIV-1) part icles and oxidize the cysteine thiolates in the NC zinc finger, We hav e characterized the effects of three such compounds on Moloney murine leukemia virus (MuLV), We find that, as with HIV-1, the compounds inac tivate cell-free MuLV particles and induce disulfide cross-linking of NC in these particles, The killed MuLV particles were found to be inca pable of synthesizing full-length viral DNA upon infection of a new ho st cell, When MuLV particles are synthesized in the presence of one of these compounds, the normal maturational cleavage of the Gag polyprot ein does not occur, The compounds have no effect on the infectivity of human foamy virus, a spumaretrovirus lacking zinc fingers in its NC p rotein, The resistance of foamy virus supports the hypothesis that the zinc fingers are the targets for inactivation of MuLV and HIV-1 by th e compounds, The absolute conservation of the zinc finger motif among oncoretroviruses and lentiviruses and the lethality of all known mutat ions altering the zinc-binding residues suggest that only the normal, wild-type structure can efficiently perform all of its functions, This possibility would make the zinc finger an ideal target for antiretrov iral agents.