Synergistic inhibition of HIV-1 envelope-mediated cell fusion by CD4-based molecules in combination with antibodies to gp120 or gp41.
CD4-based molecules were tested in combination with HIV-1-neutralizing antibodies directed against the V3 loop of gp120 or against gp41, for inhibition of HIV-1 envelope-mediated cell fusion. A virus-free cell fusion assay was developed, using Chinese hamster ovary cells that stably express HIV-1 gp120/gp41. These cells were incubated with dilutions of CD4-based molecules, antibodies, or mixtures of both, then overlaid with C8166 CD4+ T cells. Syncytia were counted and the degree of inhibition of cell fusion was determined. Synergy, additivity, or antagonism was calculated by the combination index (CI) method. The CD4-based molecules included soluble human CD4 as well as fusion proteins composed of CD4 linked to human immunoglobulin gamma 1 or gamma 2 heavy chains. Combinations of CD4-based molecules and monoclonal or polyclonal anti-V3 loop antibodies were synergistic in blocking HIV-1 envelope-mediated cell fusion (CI = 0.21-0.91 at 95% inhibition). Synergy was also observed with combinations of the CD4-based molecules and a broadly neutralizing anti-gp41 monoclonal antibody (2F5) (CI = 0.29-0.65 at 95% inhibition). These results demonstrate that molecules inhibiting HIV attachment act synergistically with molecules inhibiting HIV-1 fusion. The results suggest that CD4-based therapeutics would be more effective in patients with naturally occurring anti-V3 loop or anti-gp41 antibodies. In addition, there may be an advantage in coadministering CD4-based molecules and antibodies that block fusion, especially broadly neutralizing anti-gp41 antibodies, as a combination therapy for HIV-1 infections.
Allaway
G P
GP
Progenics Pharmaceuticals, Inc., Tarrytown, New York 10591.
Ryder
A M
AM
Beaudry
G A
GA
Maddon
P J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000494:pharmacology*; D016860:CD4 Immunoadhesins / Q000494:pharmacology*; D016466:CHO Cells; D002459:Cell Fusion; D006224:Cricetinae; D004357:Drug Synergism; D015686:Gene Products, env / Q000276:immunology*; D015726:Giant Cells; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
D015704:CD4 Antigens; D016860:CD4 Immunoadhesins; D015686:Gene Products, env; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C076613:recombinant soluble CD4