NEUTRALIZING ANTIBODIES AGAINST THE V3 LOOP OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GP120 BLOCK THE CD4-DEPENDENT AND CD4-INDEPENDENT BINDING OF VIRUS TO CELLS

The CD4 molecule is an essential receptor for human immunodeficiency v irus type 1 (HIV-1) through high-affinity interactions with the viral external envelope glycoprotein gp120. Previously, neutralizing monoclo nal antibodies (MAbs) specific to the third hypervariable domain of gp 120 (the V3 loop) have been thought to block HIV infection without aff ecting the binding of HIV particles to CD4-expressing human cells, How ever, here we demonstrate that this conclusion,vas not correct and was due to the use of soluble gp120 instead of HIV particles, Indeed, neu tralizing anti-V3 loop MAbs inhibited completely the binding and entry of HIV particles into CD4(+) human cells, In contrast, the binding of virus was only partially inhibited by neutralizing anti-CD4 MAbs agai nst the gp120 binding site in CD4, which, like the anti-V3 loop MAbs, completely inhibited HN entry and infection, Nonneutralizing control M Abs against either the V3 loop or the N or C terminus of gp120 had no significant effect on HIV binding and entry, HIV-1 particles were also found to bind human and murine cells expressing or not expressing the human CD4 molecule. Interestingly, the binding of HIV to CD4(+) murin e cells was inhibited by both anti-V3 and anti-CD4 MAbs, whereas the b inding to human and murine CD4(-) cells was affected only by anti-V3 l oop MAbs. The effect of anti-V3 loop neutralizing MAbs on the HIV bind ing to cells appears not to be the direct consequence of gp120 sheddin g from HIV particles or of a decreased affinity of CD4 or gp120 for bi nding to its surface counterpart, Taken together, our results suggest the existence of CD4-dependent and -independent binding events involve d in the attachment of HIV particles to cells; in both of these events , the V3 loop plays a critical role. As murine cells lack the specific cofactor CXCR4 for HIV-1 entry, other cell surface molecules besides CD4 might be implicated in stable binding of HIV particles to cells.