A leucine zipper motif in the cytoplasmic domain of gp41 is required for HIV-1 replication and pathogenesis in vivo

A leucine zipper motif is conserved in the cytoplasmic domain of glycoprote in gp41 (gp41c) of all HIV-1 subtypes, but is not present in HIV-2 or SIV. The second leucine residue of the leucine zipper was mutated (L95R) to dete rmine the role of this motif in HIV-1 replication and pathogenesis. The L95 R mutant replicated to wild-type levels in activated peripheral blood monon uclear cells and CEMx174 cells. However, L95R replication was impaired in S upT1 cells and in the SCID-hu Thy/Liv mouse. Although the infectivity of wi ld-type virions and that of L95R mutant virions were equally sensitive to h eat treatment, we found that L95R produced more defective virions, due to r educed surface expression and virion incorporation of the env glycoprotein. These results suggest that the L95 residue in the leucine zipper of gp41c of HIV-1 plays an important role in the env expression and virion incorpora tion that is required for viral replication and pathogenesis in the SCID-hu Thy/Liv mouse. The leucine zipper motif In gp41c may provide a novel anti- HIV-1 target. (C) 2001 Academic Press.