Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.

Myocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with altered diastolic conformation. These novel insights significantly improve understanding of contractile dysfunction at a level of noninvasive interrogation not previously available in humans.

BackgroundCardiac diffusion tensor imaging (cDTI) measures the magnitudes and directions of intramyocardial water diffusion. Assuming the cross-myocyte components to be constrained by the laminar microstructures of myocardium, we hypothesized that cDTI at two cardiac phases might identify any abnormalities of laminar orientation and mobility in hypertrophic cardiomyopathy (HCM).MethodsWe performed cDTI in vivo at 3 Tesla at end-systole and late diastole in 11 healthy controls and 11 patients with HCM, as well as late gadolinium enhancement (LGE) for detection of regional fibrosis.ResultsVoxel-wise analysis of diffusion tensors relative to left ventricular coordinates showed expected transmural changes of myocardial helix-angle, with no significant differences between phases or between HCM and control groups. In controls, the angle of the second eigenvector of diffusion (E2A) relative to the local wall tangent plane was larger in systole than diastole, in accord with previously reported changes of laminar orientation. HCM hearts showed higher than normal global E2A in systole (63.9° vs 56.4° controls, p = 0.026) and markedly raised E2A in diastole (46.8° vs 24.0° controls, p < 0.001). In hypertrophic regions, E2A retained a high, systole-like angulation even in diastole, independent of LGE, while regions of normal wall thickness did not (LGE present 57.8°, p = 0.0028, LGE absent 54.8°, p = 0.0022 vs normal thickness 38.1°).ConclusionsIn healthy controls, the angles of cross-myocyte components of diffusion were consistent with previously reported transmural orientations of laminar microstructures and their changes with contraction. In HCM, especially in hypertrophic regions, they were consistent with hypercontraction in systole and failure of relaxation in diastole. Further investigation of this finding is required as previously postulated effects of strain might be a confounding factor.Electronic supplementary materialThe online version of this article (doi:10.1186/s12968-014-0087-8) contains supplementary material, which is available to authorized users.