Trispecific antibody targeting HIV-1 and T cells activates and eliminates latently-infected cells in HIV/SHIV infections.

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 <sup>+</sup> and CD8 <sup>+</sup> T cells. Co-culturing CD4 <sup>+</sup> with autologous CD8 <sup>+</sup> T cells from ART-suppressed HIV <sup>+</sup> donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 <sup>+</sup> T cells. This trispecific antibody mediates CD4 <sup>+</sup> and CD8 <sup>+</sup> T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection

Analyzing multitarget activity landscapes using protein-ligand interaction fingerprints: interaction cliffs.

This is the original submitted version, before peer review. The final peer-reviewed version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ci500721x.Activity landscape modeling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs. Nevertheless, the interpretation of some landscape features, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modeling of 507 ligand-kinase complexes (from the KLIFS database) including IFP, which facilitates the analysis and interpretation of activity cliffs. Here we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information on ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity but have a large potency difference of the ligands. Moreover, the information retrieved regarding the specific interaction allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs provides a structure-based understanding of some activity landscape features. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.M-L is very grateful to CONACyT (No. 217442/312933) and the Cambridge Overseas Trust for funding. AB thanks Unilever for funding and the European Research Council for a Starting Grant (ERC-2013- StG-336159 MIXTURE). J.L.M-F. is grateful to the School of Chemistry, Department of Pharmacy of the National Autonomous University of Mexico (UNAM) for support. This work was supported by a scholarship from the Secretariat of Public Education and the Mexican government

Increased water content in periventricular caps in patients without acute hydrocephalus

BACKGROUND AND PURPOSE: Periventricular caps are a common finding on MR imaging and are believed to reflect focally increased interstitial water content due to dysfunctional transependymal transportation rather than ischemic-gliotic changes. We compared the quantitative water content of periventricular caps and microvascular white matter lesions, hypothesizing that periventricular caps associated with increased interstitial fluid content display higher water content than white matter lesions and are therefore differentiable from microvascular white matter lesions by measurement of the water content.MATERIALS AND METHODS: In a prospective study, we compared the water content of periventricular caps and white matter lesions in 50 patients using a quantitative multiple-echo, gradient-echo MR imaging water-mapping sequence.RESULTS: The water content of periventricular caps was significantly higher than that of white matter lesions (P = .002). Compared with normal white matter, the mean water content of periventricular caps was 17% ± 5% higher and the mean water content of white matter lesions was 11% ± 4% higher. Receiver operating characteristic analysis revealed that areas in which water content was 15% higher compared with normal white matter correspond to periventricular caps rather than white matter lesions, with a specificity of 93% and a sensitivity of 60% (P < .001). There was no significant correlation between the water content of periventricular caps and whole-brain volume (P = .275), white matter volume (P = .243), gray matter volume (P = .548), lateral ventricle volume (P = .800), white matter lesion volume (P = .081), periventricular cap volume (P = .081), and age (P = .224).CONCLUSIONS: Quantitative MR imaging allows differentiation between periventricular caps and white matter lesions. Water content quantification of T2-hyperintense lesions may be a useful additional tool for the characterization and differentiation of T2-hyperintense diseases