V3 loop-derived multibranched peptides as inhibitors of HIV infection in CD4(+) and CD4(-) cells

The V3 loop is one of the variable domains of the HIV-1 surface envelope glycoprotein gp120 that mainly generates isolate-specific neutralizing antibodies. These anti-V3 antibodies presumably interfere with the function of the V3 loop that is thought to be involved in virus-cell fusion. In an approach to neutralize HIV infection, monomeric linear or cyclic V3 loop-related peptides have experimentally been used to impair the fusion process. The reported results are contradictory, including peptide-induced enhancement of viral infectivity. Fn order to develop a new strategy, synthetic polymeric constructions (SPCs) including the V3 loop consensus sequence of HIV-1 North American/European isolates (i.e. GPGRAF) have been synthesized and tested for antiviral activity. The rationale for using SPCs instead of monomeric peptides was a presumed enhancement of ligand avidity due to multivalence. Among the SPCs tested, SPC3 (eight GPGRAF motifs radially branched on an uncharged polylysine core matrix) was found to inhibit the infection of human CD4(+) lymphocytes and macrophages, as well as CD4(-)/galactosylceramide (GalCer)-expressing epithelial cells by distantly related laboratory strains and clinical isolates of HIV-1 and HIV-2. SPC3 affected HIV-1 infection by two distinct mechanisms, depending on the cell-type: (i) postbinding inhibition of HIV-1 entry into CD4(+) lymphocytes; and (ii) prevention of GalCer-mediated HIV-1 attachment to the surface of CD4(-)/GalCer(+) cells. SPC3 may therefore represent the first of a novel class of anti-HIV therapeutic agents able to neutralize a wide range of HIV isolates in both CD4(+) and CD4(-) susceptible cells. The antiviral properties of this peptide are currently being evaluated in HIV-1-infected patients (phase II clinical trials).