Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy.

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Highlights from the Tenth International Workshop on HIV Persistence during Therapy, December 13-16, 2022, Miami, Florida-USA.

The International Workshop on HIV Persistence during Therapy provides a forum in which HIV/AIDS researchers gather to share the latest research findings related to viral reservoirs and cure. The Tenth Workshop, which was attended by over 400 delegates, extended over 4 days and comprised eight sessions covering topics from the basic science of viral persistence to therapeutic approaches to HIV cure. Furthermore, satellite sessions on the first day of the Conference featuring cure research endeavours being pursued by the Bill and Melinda Gates Foundation as well as those being coordinated under the National Institutes of Health Martin Delaney Collaboratory program, provided important updates on research advances being made in these initiatives. As with previous conferences, the International Workshop on HIV Persistence during Therapy is primarily abstract-driven with only one invited talk for each of the sessions. This format, therefore, increases the number of presentations from early-stage investigators. Furthermore, presentations by Community representatives illustrated approaches to creating cure research literacy with effective messaging for the Community. The following article offers a synopsis of the meeting sessions. Due to space constraints, some presentations may have only been briefly discussed. Nevertheless, the Workshop abstracts can be found online (https://www/sciencedirect.com/journal/journal-of-virus-eradication/vol/8/suppl/S).

The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function.

Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir.

The primary auditory cortex in cetacean and human brain: a comparative analysis of neurofilament protein-containing pyramidal neurons.

To extend our investigation of the anatomy of sensory systems in highly adapted aquatic and terrestrial mammals, we have analyzed the distribution of a particular population of efferent neurons in the cetacean and human primary auditory cortex using an antibody to non-phosphorylated neurofilament protein (SMI32). The neurofilament protein triplet is differentially distributed within neuronal subpopulations in the primate and cetacean neocortex. In primates, it appears that the somatodendritic domain of a subset of pyramidal neurons furnishing specific corticocortical connections contains high concentrations of neurofilament protein. In the human primary auditory cortex these neurons are located in layers III, V and VI, whereas in cetaceans they are concentrated almost exclusively in the cortical efferent layer IIIc/V. Previous analyses have shown that SMI32 immunoreactivity in the cetacean neocortex is uniformly distributed among functionally different areas, while in human neocortex, the distribution of SMI32-positive neurons exhibit a high degree of regional and laminar specialization that is correlated with the functional and anatomical diversity of the cortical areas. In addition, the overall distribution of SMI32-immunoreactive neurons in the cetacean neocortex is comparable to that observed in paralimbic areas of the human, suggesting that the cetacean neocortex has retained many features of phylogenetically older cortical regions.

Posterior cortical atrophy in Alzheimer's disease: analysis of a new case and re-evaluation of a historical report.

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)

Selective distribution of kainate receptor subunit immunoreactivity in monkey neocortex revealed by a monoclonal antibody that recognizes glutamate receptor subunits GluR5/6/7.

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.