We have isolated and characterized human monoclonal antibody 2G12 to the gp120 surface glycoprotein of human immunodeficiency virus type 1 (HIV-1). This antibody potently and broadly neutralizes primary and T-cell line-adapted clade B strains of HIV-1 in a peripheral blood mononuclear cell-based assay and inhibits syncytium formation in the AA-2 cell line. Furthermore, 2G12 possesses neutralizing activity against strains from clade A but not from clade E. Complement-and antibody-dependent cellular cytotoxicity-activating functions of 2G12 were also defined. The gp120 epitope recognized by 2G12 was found to be distinctive; binding of 2G12 to LAI recombinant gp120 was abolished by amino acid substitutions removing N-linked carbohydrates in the C2, C3, V4, and C4 regions of gp120. This gp120 mutant recognition pattern has not previously been observed, indicating that the 2G12 epitope is unusual. Consistent with this, antibodies able to block 2G12 binding to recombinant gp120 were not detected in significant quantities in 16 HIV-positive human serum samples.

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␥-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer's disease (AD). ␥-Secretase inhibitors reduce brain ␤-amyloid peptide (A␤), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human ␤-amyloid precursor protein (APP) are valuable models to examine the dynamics of A␤ changes with ␥-secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid, a ␥-secretase inhibitor, showed doseand time dependent reductions of A␤ in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF A␤ levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of A␤ in plaques showed reductions in CSF A␤ in the absence of measurable changes in plaque A␤ in the brain after up to 2 weeks of treatment. Hence, CSF A␤ levels were a valuable measure of ␥-secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in the maturation of CD8ϩ thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for ␥-secretase inhibitors to reduce brain A␤ without causing Notch-mediated toxicity.Diagnosis of AD is based on key pathological features at autopsy in the presence of dementia: loss of neuronal mass, intracellular tangles, and extracellular plaques. Plaques are composed predominantly of A␤. A␤ has both N-and C-terminal heterogeneity, with the C terminus usually ending at residues 40 or 42. Although A␤40 is 80 to 90% of the total, A␤42 is most associated with disease and is predominant in plaques. A␤ is produced by two cleavage events in APP (Wolfe, 2001). ␤-Secretase, now identified as ␤-site APP cleaving enzyme, makes the initial N-terminal cleavage, releasing a soluble N-terminal form of APP. The remaining, membrane-bound C-terminal fragment (CTF) of APP is cleaved by ␥-secretase to release soluble A␤ along with the APP intracellular domain. Alternatively, APP can This research was supported by Bristol-Myers Squibb and SIBIA Neurosciences, Inc.Article, publication date, and citation information can be found at

BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the "phenylalanine 43 cavity" and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs.