Recombinant Human CLEC5A protein (a.a. 28-188) [His]

Human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) is a viral protein that promotes transcription of the HIV genome and possesses cell-signaling properties. Long-term exposure of central nervous system (CNS) tissue to HIV-1 Tat is theorized to contribute to HIV-associated neurodegenerative disorder (HAND). In the current study, we sought to directly evaluate the effect of HIV-1 Tat expression on the intrinsic electrophysiological properties of pyramidal neurons located in layer 2/3 of the medial prefrontal cortex and in area CA1 of the hippocampus. Toward that end, we drove Tat expression with doxycycline (100 mg.kg(-1).day(-1) ip) in inducible Tat (iTat) transgenic mice for 7 days and then performed single-cell electrophysiological studies in acute tissue slices made through the prefrontal cortex and hippocampus. Control experiments were performed in doxycycline-treated G-tg mice, which retain the tetracycline-sensitive promoter but do not express Tat. Our results indicated that the predominant effects of HIV-1 Tat expression are excitatory in medial prefrontal cortical pyramidal neurons yet inhibitory in hippocampal pyramidal neurons. Notably, in these two populations, HIV-1 Tat expression produced differential effects on neuronal gain, membrane time constant, resting membrane potential, and rheobase. Similarly, we also observed distinct effects on action potential kinetics and afterhyperpolarization, as well as on the current-voltage relationship in subthreshold voltage ranges. Collectively, these data provide mechanistic evidence of complex and region-specific changes in neuronal physiology by which HIV-1 Tat protein may promote cognitive deficits associated with HAND. NEW & NOTEWORTHY We drove expression of human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) protein in inducible Tat (iTat) transgenic mice for 7 days and then examined the effects on the intrinsic electrophysiological properties of pyramidal neurons located in the medial prefrontal cortex (mPFC) and in the hippocampus. Our results reveal a variety of specific changes that promote increased intrinsic excitability of layer II/III mPFC pyramidal neurons and decreased intrinsic excitability of hippocampal CA1 pyramidal neurons, highlighting both cell type and region-specific effects.

Objective: To determine whether viral suppressive capacity (VSC) of CD8(+) T cells can be boosted by stimulation with HIV-1 peptides and whether the ability to control HIV-1 replication correlates with immunological (cytokine production and CD8(+) T-cell phenotype) and viral reservoir measures (total HIV-1 DNA and cell-associated RNA) in well treated HIV-infected chronic progressors. Design: We compared VSC of peripheral CD8(+) T cells to cytokine production profile in response to peptide stimulation, detailed phenotype (17-color flow-cytometry), reservoir size (total HIV-1 DNA), basal viral transcription (unspliced cell-associated RNA) and inducible viral transcription (tat/rev induced limiting dilution assay) in 36 HIV+patients on cART and six healthy donors. Results: We found that the VSC of CD8(+) T cells can be increased by prior stimulation with a pool of consensus HIV-1 gag peptides in a significant proportion of progressor patients. We also found that VSC after peptide stimulation was correlated with higher expression of immune checkpoint markers on subsets of terminally differentiated effector memory (TEMRA) CD8(+) T cells as well as with production of IFN-gamma, TNF-alpha and IL-10. We did not find a correlation between VSC and viral reservoir measures. Conclusion: These results add to a small body of evidence that the capacity of CD8(+) T cells to suppress viral replication is increased after stimulation with HIV-1 peptides. Interestingly, this VSC was correlated with expression of immune checkpoint markers, which are generally considered to be markers of exhaustion. Our findings may guide further investigations into immune phenotypes correlated with viral suppression. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.