SYNERGISTIC INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE GLYCOPROTEIN-MEDIATED CELL-FUSION AND INFECTION BY AN ANTIBODY TO CD4 DOMAIN-2 IN COMBINATION WITH ANTI-GP120 ANTIBODIES

Antibodies to several epitopes of the human immunodeficiency virus typ e 1 (HIV 1) envelope glycoprotein (gp120-gp41) can synergize in inhibi ting HIV-1 infection, In the present study we tested the ability of a monoclonal antibody (MAb), 5A8, which interacts with CD4 domain 2, and other CD4-specific MAbs to synergize with antibodies against gp120. W e have previously found that 5A8 inhibits HIV-1 entry without interfer ing with gp120 binding to CD4, presumably by affecting a postbinding m embrane fusion event. Because antibodies to the gp120 V3 loop also aff ect post-CD4-gp120-binding events, 5A8 was first tested in combination with anti-V3 loop antibodies for possible synergy. The anti-V3 loop a ntibodies 0.5 beta, NEA-9205, and 110.5 acted synergistically with 5A8 in inhibiting syncytium formation between gp120-gp41- and CD4-express ing cells. A human MAb to an epitope of gp120 involved in CD4 binding, IAM 120-1B1, and another anti-CD4 binding site antibody, PC39,13, als o exerted synergistic effects in combination with 5A8. Similarly, an a ntibody against the gp120 binding site on CD4, 6H10, acted synergistic ally with an anti-V3 loop antibody, NEA-9205. However, a control anti- CD4 antibody, OKT4, which does not significantly inhibit syncytium for mation alone, produced only an additive effect when combined with NEA- 9205. Serum from HIV-1-infected individuals, which presumably contains antibodies to the V3 loop and the CD4 binding site, exhibited a stron g synergistic effect,vith 5A8 in inhibiting infection by a patient HIV -1 isolate (0104B) and in blocking syncytium formation, These results indicate that therapeutics based on antibodies affecting both non-gp12 0 binding and gp120 binding epitopes of the target receptor molecule, CD4, could be efficient in patients who already contain anti-gp120 ant ibodies and could also be used to enhance passive immunization against HIV-1 in combination with anti-gp120 antibodies.