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 glycoprotein 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 determine the role of this motif in HIV-1 replication and pathogenesis. The L95R mutant replicated to wild-type levels in activated peripheral blood mononuclear cells and CEMx174 cells. However, L95R replication was impaired in SupT1 cells and in the SCID-hu Thy/Liv mouse. Although the infectivity of wild-type virions and that of L95R mutant virions were equally sensitive to heat treatment, we found that L95R produced more defective virions, due to reduced 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 incorporation 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