M. to be acknowledged after fixation was inversely related to the entropic changes associated with ligand binding. In addition, fixation apparently limited the access of antibodies to the V3 loop and gp41-interactive surface of gp120 only in the context of trimeric envelope glycoproteins. The results support a model in which the unliganded monomeric and trimeric HIV-1 envelope glycoproteins sample several different conformations. Depletion of particular fixed conformations by antibodies allowed characterization of the associations among the conformational says. Potent neutralizing antibodies recognize the greatest number of conformations and therefore can bind the virion envelope glycoproteins more rapidly and completely than weakly neutralizing antibodies. Thus, the conformational flexibility of the HIV-1 envelope glycoproteins creates thermodynamic Goat Polyclonal to Mouse IgG and kinetic barriers to neutralization by antibodies directed against the receptor-binding regions of gp120. Human immunodeficiency computer virus type 1 (HIV-1) is the etiologic agent of most cases of AIDS (3, 23). The epidemic of HIV-1 infections continues to expand globally, with more than 40 million humans currently infected by the computer virus (27a). Modalities to prevent transmission of HIV-1 are urgently needed to curb the AIDS epidemic. The early events in HIV-1 contamination, which occur before the formation of the provirus, serve as attractive targets in the 25-Hydroxy VD2-D6 development of prophylactic approaches, including vaccines. HIV-1 entry, which occurs in water-soluble compartments readily accessible to drugs and involves well-defined viral and host molecules, has generated much interest as a target for intervention. HIV-1 entry into the host cell is usually mediated by the viral envelope glycoproteins, which are derived by proteolytic cleavage of a trimeric, glycosylated gp160 envelope glycoprotein precursor (2, 46). The resulting mature envelope glycoproteins, gp120 and gp41, constitute a trimeric complex around the virion surface that is anchored by the membrane-spanning segments of the gp41 transmembrane envelope glycoproteins (6, 7, 16, 17, 37, 42, 58). 25-Hydroxy VD2-D6 The gp120 exterior envelope glycoprotein is usually retained around the trimer via labile, noncovalent interactions with the gp41 ectodomain (26). The gp120 glycoprotein is the most uncovered element around the trimer and binds the initial receptor, CD4 (11, 28). CD4 binding triggers conformational changes in gp120 that promote its conversation with one of the chemokine receptors, CCR5 or CXCR4 (1, 10, 13-15, 19, 54, 61). CD4 binding also induces conformational changes within the assembled HIV-1 envelope glycoprotein trimer that result in the exposure of a helical heptad repeat (HR1) segment of the gp41 ectodomain (22, 25, 29, 50). Eventually, the conformational transition of the gp41 ectodomain into a six-helix bundle composed of the HR1 and HR2 heptad repeat regions is thought to provide the energy needed to fuse the viral and target cell membranes (7, 37, 58). The binding of an antibody molecule to the HIV-1 envelope glycoprotein complex results in neutralization of the function of the bound trimer (69). Thus, the ability of HIV-1 to establish persistent infections in human hosts requires envelope glycoprotein characteristics that minimize the elicitation and efficacy of neutralizing antibodies (4, 64). Indeed, during natural HIV-1 infection, antibodies that potently neutralize primary clinical HIV-1 isolates are only rarely elicited. Several features of the HIV-1 gp120 envelope glycoprotein that are important in evasion of the host immune response include heavy glycosylation, sequence variability, and conformational masking of conserved epitopes involved in receptor binding (30, 25-Hydroxy VD2-D6 38, 57, 64). The latter property has been deduced from thermodynamic studies that suggest that monomeric gp120 experiences unusually large decreases in entropy upon binding CD4 and many weakly neutralizing antibodies (30, 41). These ligands are hypothesized to fix the gp120 glycoprotein, which is usually proposed to be conformationally flexible in the free, unliganded state, into a single conformation, thus accounting for the observed decreases in entropy. By contrast, the rare potent neutralizing antibodies bind gp120 with small changes in entropy (30). Although these thermodynamic studies were carried out with monomeric gp120, the observed correlation between the entropic change associated with antibody binding and neutralization potency implies relevance to the functional HIV-1 envelope glycoprotein trimer as well (30). Presumably, the large, thermodynamically unfavorable changes that occur in the context of the envelope glycoprotein trimer minimize effective antibody binding to the computer virus. Full-length HIV-1 gp120 has eluded structural analysis. However, deletion of the large V1, V2, and V3 variable.