SYNERGISTIC NEUTRALIZATION OF SIMIAN-HUMAN IMMUNODEFICIENCY VIRUS SHIV-VPU(-ANTIBODIES AND HIGH-TITER ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IMMUNOGLOBULINS() BY TRIPLE AND QUADRUPLE COMBINATIONS OF HUMAN MONOCLONAL)

We have tested triple and quadruple combinations of human monoclonal a ntibodies (MAbs), which are directed against various epitopes on human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins, and a h igh-titer anti-HIV-1 human immunoglobulin (HIVIG) preparation for thei r abilities to neutralize a chimeric simian-human immunodeficiency vir us (SHIV-vpu(+)). This virus encodes the HIV-1 strain IIIB env, tat, r ev, and vpu genes. The quantitative nature of the Chou-Talalay method (Adv. Enzyme Regul. 22:27-55, 1984) allows ranking of various combinat ions under identical experimental conditions. Of all triple combinatio ns tested, the most potent neutralization was seen with MAbs 694/98D p lus 2F5 plus 2G12 (directed against domains on V3, gp41, and gp120, re spectively) as measured by the total MAb concentration required to rea ch 90% neutralization (90% effective concentration [EC90], 2.0 mu g/ml ). All triple combinations involving MAbs and/or HIVIG that were teste d yielded synergy with combination index values of <1; the dose reduct ion indices (DRIs) ranged from 3.1 to 26.2 at 90% neutralization. When four MAbs (the previous three plus MAb F105, directed against the CD4 binding site) were combined, higher neutralization potency (EC90, 1.8 mu g/ml) and a higher degree of synergy compared to any triple combin ation were seen. The mean DRIs of the quadruple combination were appro ximately twice that of the most synergistic triple combination. We con clude that human MAbs targeting different HIV-1 envelope glycoprotein epitopes exhibit strong synergy when used in combination, a fact that could be exploited clinically for passive immunoprophylaxis against HI V-1.