Here we demonstrate that a combination of tenofovir, emtricitabine, and raltegravir effectively suppresses peripheral and systemic HIV replication in humanized BLT mice. We also demonstrate that antiretroviral therapy (ART)-treated humanized BLT mice harbor latently infected resting human CD4 ؉ T cells that can be induced ex vivo to produce HIV. We observed that the levels of infected resting human CD4 ؉ T cells present in BLT mice are within the range of those observed circulating in patients undergoing suppressive ART. These results demonstrate the potential of humanized BLT mice as an attractive model for testing the in vivo efficacy of novel HIV eradication strategies.

Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined.

The prospective addition of valproic acid to stable antiretroviral therapy reduced the frequency of resting CD4+ T-cell infection in a minority of volunteers. In patients in whom resting CD4+ T-cell infection depletion was observed, viremia was rarely detectable by single copy assay.

A monoclonal antibody (4F5) was generated against a portion of the putative extracellular domain of glutamate receptor subunit GluR5. Western blot analyses and immunocytochemistry of transfected human embryonic kidney 293 cells confirmed that monoclonal antibody 4F5 was specific for GluR5, -6, and -7 (the three identified members of the kainate receptor subunit class), but did not recognize GluR1, -2, or -3 (the AMPA/kainate receptor subunit class). The antibody was subsequently used to examine immunocytochemically the regional, laminar, and cellular distribution of GluR5/6/7 receptor subunits at the light and electron microscopic levels in monkey neocortex. Receptor subunit immunoreactivity was present throughout all cortical areas examined, but exhibited marked cellular, laminar, and regional specificity. Typically, pyramidal cell somata and apical dendrites were well stained. Electron microscopy revealed an extensive cytoplasmic localization of GluR5/6/7 immunoprecipitate, with intense staining of many postsynaptic densities, all of which were associated with asymmetric synapses located on dendritic shafts or dendritic spines. There was no evidence of stained glial cells or presynaptic axon terminals. In most areas, labeled cells and dendrites were concentrated in layers II, III, and V while layers I, IV, and VI typically possessed the fewest and/or least intensely stained elements. A consistent feature in many areas was groups of clustered layer V pyramidal cells and bundles of ascending apical dendrites. Regionally, motor areas and higher-order association areas of the frontal, parietal, and occipital lobes were more densely stained than primary sensory areas (somatic sensory and visual cortex), which was confirmed quantitatively. These data indicate a high degree of selectivity in the distribution of kainate receptors composed of GluR5/6/7 subunits, and suggest that functional specificity and diversity in the ubiquitous excitatory amino acid-utilizing axonal systems in neocortex are achieved in part by the differential association of particular glutamate receptor subunits with specific cortical circuits. In addition, the regional, laminar, and morphological characteristics of GluR5/6/7-immunoreactive neurons bear a strong similarity to those of the neocortical neurons with heightened vulnerability in certain neurodegenerative disorders.

The novel mechanism through which HMBA disrupts latent HIV-1 infection involves 2 cellular kinases that may be therapeutically exploited to induce expression of persistent proviral HIV-1.

Disturbances of visual function are not uncommon in Alzheimer's disease and several cases with complex impairment of visuospatial abilities have been described. For instance, posterior cortical atrophy has been demonstrated in cases displaying Balint's syndrome as the first symptom of the dementing illness. Such cases showed very high lesion counts in the occipital cortex, as well as in visual association regions in the posterior parietal and posterior cingulate cortex, whereas the prefrontal cortex was consistently less severely involved than usually observed in Alzheimer's disease. This suggests that the distribution of the lesions had been shifted to specific elements of the visual system. In the present study, we report the quantitative analysis of a new case of Alzheimer's disease with possible Balint's syndrome and re-evaluate a case originally described in 1945. The distribution of lesion in these two cases parallels previous observations of Alzheimer's disease cases with early visual impairment. Both cases displayed very high densities of neurofibrillary tangles and senile plaques in the primary visual cortex, secondary visual cortex, visual association areas of the dorsal occipital and posterior parietal lobe and in the posterior cingulate cortex, whereas the prefrontal and inferior temporal regions were comparatively less affected. These cases may define clinical subgroups of Alzheimer's disease and suggest that the breakdown of corticocortical projections that is known to occur in dementia may involve select components of specific functional systems in certain cases. In particular, pathways that subserve motion detection and visuospatial analysis appear to be dramatically affected in these cases presenting with Balint's syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Finally, HMBA interferes with cell proliferation and activation; it suppressed expression of Ki67 and CD25 and in PBMCs exposed to mitogen. As HMBA has been tested in oncology trials, its unusual properties make it a useful reagent for future studies of HIV promoter regulation and a novel prototype molecule for therapeutics that abort the latent proviral state of chronic HIV infection.

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