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1.  β-Catenin Signaling Mediates CD4 Expression on Mature CD8+ T Cells 
Upon activation, a subset of mature human CD8+ T cells re-expresses CD4 dimly. This CD4dimCD8bright T cell population is genuine and enriched in antiviral CD8+ T cell responses. The signaling pathway that leads to CD4 re-expression on mature CD8+ T cells is not clear. Given that Wnt/β-catenin signaling plays a critical role in the transition of CD4−CD8− to CD4+CD8+ thymocytes, we determined whether β-catenin mediates CD4 expression on mature CD8+ T cells. We demonstrate that active β-catenin expression is 20-fold higher on CD4dimCD8bright than CD4−CD8+ T cells. Activation of β-catenin signaling, through LiCl or transfection with a constitutively active construct of β-catenin, induced CD4 on CD8+ T cells by ~10-fold. Conversely, inhibition of β-catenin signaling through transfection with a dominant-negative construct for T cell factor-4, a downstream effector of β-catenin signaling, diminished CD4 expression on CD8+ T cells by 50% in response to T cell activation. β-catenin–mediated induction of CD4 on CD8+ T cells is transcriptionally regulated, as it induced CD4 mRNA, and T cell factor/lymphoid enhancer factor sites were identified within the human CD4 promoter. Further, β-catenin expression induced the antiapoptotic factor BcL-xL, suggesting that β-catenin may mediate protection against activation-induced cell death. Collectively, these data demonstrate that β-catenin is critical in inducing CD4 expression on mature CD8+ T cells, suggesting that it is a common pathway for CD4 upregulation among thymocytes and mature CD8+ T cells.
doi:10.4049/jimmunol.0902572
PMCID: PMC3963465  PMID: 20631314
2.  Porcupine Is Not Required for the Production of the Majority of Wnts from Primary Human Astrocytes and CD8+ T Cells 
PLoS ONE  2014;9(3):e92159.
Wnts are small secreted glycoproteins that are highly conserved among species. To date, 19 Wnts have been described, which initiate a signal transduction cascade that is either β-catenin dependent or independent, culminating in the regulation of hundreds of target genes. Extracellular release of Wnts is dependent on lipidation of Wnts by porcupine, a membrane-bound-O-acyltransferase protein in the endoplasmic reticulum. Studies demonstrating the requirement of porcupine for Wnts production are based on cell line and non-human primary cells. We evaluated the requirement for porcupine for Wnts production in human primary astrocytes and CD8+ T cells. Using IWP-2, an inhibitor of porcupine, or siRNA targeting porcupine, we demonstrate that porcupine is not required for the release of Wnt 1, 3, 5b, 6,7a, 10b, and 16a. While IWP had no effect on Wnt 2b release, knockdown of porcupine by siRNA reduced Wnt 2b release by 60%. These data indicate that porcupine-mediated production of Wnts is context dependent and is not required for all Wnts production, suggesting that alternative mechanisms exist for Wnts production.
doi:10.1371/journal.pone.0092159
PMCID: PMC3960167  PMID: 24647048
3.  Interplay between Wnt/β-catenin signaling and HIV: Virologic and biologic consequences in the CNS 
Considerable studies have evaluated the interaction between Wnt/β-catenin signaling and numerous cellular processes. Emerging findings now demonstrate that Wnt/β-catenin signaling interacts with the life cycle of the Human Immunodeficiency Virus type 1 (HIV-1). Wnt/β-catenin is a restrictive pathway to HIV replication in multiple target cells including peripheral blood mononuclear cells and astrocytes. The molecular interaction between Wnt/β-catenin signaling and HIV has been evaluated in astrocytes because they express robust level of this pathway. The cross talk that occurs between these two components has significant biologic consequences to HIV-mediated neuropathogenesis. This perspective highlights current knowledge regarding the interaction between Wnt/β-catenin signaling and HIV, the interplay between these two pathways as it impacts key features of NeuroAIDS, and provides an assessment of knowledge gaps in the field that could propel our understanding of this interaction to inform novel strategies to exploit Wnt signaling for therapeutic intervention in HIV/NeuroAIDS.
doi:10.1007/s11481-012-9411-y
PMCID: PMC3518628  PMID: 23065461
4.  Role of β-Catenin/TCF-4 Signaling in HIV Replication and Pathogenesis: Insights to Informing Novel Anti-HIV Molecular Therapeutics 
A greater understanding of the interaction between HIV and host signaling pathways that restrict virus production may lead to new methods to purge virus from latent reservoirs and enhance survival/function of cells targeted by HIV. This review highlights the role of the Wnt/β-catenin pathway as a host factor that represses HIV replication in multiple targets, especially those relevant to HIV in the central nervous system.
doi:10.1007/s11481-011-9266-7
PMCID: PMC3836044  PMID: 21384147
HIV neuropathogenesis; Astrocyte; Signaling pathway
5.  Entrapment of recent thymic emigrants in lymphoid tissues from HIV-infected patients: association with HIV cellular viral load 
AIDS (London, England)  2002;16(16):2119-2127.
Objective(s)
Depletion of thymus derived naive T-cells is a feature of HIV infection. Here the impact of HIV infection on the compartmentalization of recent thymic emigrants of (RTE) and naive T-cells was examined.
Methods
Peripheral blood mononuclear cells (PBMC) and lymphoid tissue (LT) from 43 HIV-infected patients and 12 controls were examined for RTE distribution by measuring coding joint T-cell receptor excisional circles (cjTREC) by PCR and naive and memory T-cell subsets and adhesion molecules (L-selection, LFA-1) by flow cytometry.
Results
In HIV-infected patients, the RTE as quantified by cjTRECs in CD4 LT cells were significantly higher than in PBMC. Their values, however, were less than in control subjects, in both the LT and PBMC compartments. This was associated with an increase in L-selectin and LFA-1 expression on LT derived T cells. In PBMC, a significant positive relationship between TREC and naive CD4 cells and an inverse relationship between TREC and cellular viral load (CVL) was observed. Whereas in LT, there was a positive relationship between cjTREC and both naive CD4 cell percentage and CVL.
Conclusions
Collectively, the data suggests that LT is a significant reservoir for RTE. The RTE appeared to be entrapped in LT from HIV-infected subjects. Such entrapment is probably a response to the high viral load in these tissues. These observations may partially explain the decline in RTE observed in the peripheral blood of HIV-infected patients, and the delay in recovery of naive cells in blood after initiation of HAART.
PMCID: PMC3738871  PMID: 12409732
Naive T cells; recent thymic emigrants; TRECs; HIV; AIDS
6.  Methamphetamine and HIV-1 Tat Down Regulate β-catenin Signaling: Implications for Methampetamine Abuse and HIV-1 Co-morbidity 
Methamphetamine (Meth) abuse exacerbates HIV-1-associated neurocognitive disorders (HAND). The underlying mechanism for this effect is not entirely clear but likely involves cooperation between Meth and HIV-1 virotoxins, such as the transactivator of transcription, Tat. HIV-1 Tat mediates damage in the CNS by inducing inflammatory processes including astrogliosis. Wnt/β catenin signaling regulates survival processes for both neurons and astrocytes. Here, we evaluated the impact of Meth on the Wnt/β-catenin pathway in astrocytes transfected with Tat. Meth and Tat downregulated Wnt/β-catenin signaling by >50%, as measured by TOPflash reporter activity in both an astrocytoma cell line and primary human fetal astrocytes. Meth and Tat also down-regulated LEF-1 transcript by >30%. LEF-1 is a key partner of β-catenin to regulate cognate gene expression. Interestingly, estrogen, which induces β-catenin signaling in a cell-type specific manner, at physiological concentrations of 1.5 and 3 nM normalized individual Meth and Tat effects on β-catenin signaling but not their combined effects. These findings suggest that Meth and Tat likely exert different mechanisms to mediate down regulation of β-catenin signaling. The consequences of which may contribute to the pathophysiologic effects of HIV-1 and Meth co-morbidity in the CNS.
doi:10.1007/s11481-011-9295-2
PMCID: PMC3714216  PMID: 21744004
Methamphetamine; HIV; Tat; β-catenin signaling; Astrocytes
7.  Wnt/β-catenin and its Diverse Physiological Cell Signaling Pathways in Neurodegenerative and Neuropsychiatric Disorders 
Wnt signaling is a fundamental pathway in embryogenesis which is evolutionary conserved from metazoans to humans. Much of our understanding of Wnt signaling events emerged from key developmental studies in drosophila, zebra fish, xenopus, and mice. Considerable data now exists on the role of Wnt signaling beyond these developmental processes and in particular its role in health and disease. The focus of this special issue is on Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. This special issue is composed of six reviews and two original articles selected to highlight recent advances in the role of Wnt signaling in CNS embryonic development, in adult brain function, in neurodegenerative conditions such as Alzheimer’s disease, schizophrenia, NeuroAIDS, and in gliomas. The finding that β-catenin can translocate to the nucleus where it binds to TCF/LEF transcription factors to regulate target gene expression was a seminal observation that linked β-catenin/LEF to T cell development and differentiation. We also provide a nostalgic look on recent advances in role of Wnts in T cell development and maturation. These reviews highlight the extensive body of work in these thematic areas as well as identify knowledge gaps, where appropriate. Understanding Wnt function under healthy and diseased conditions may provide a therapeutic resource, albeit it a challenging one, in diseases where dysfunctional and/or diminished Wnt signaling is a prominent player in the disease process.
doi:10.1007/s11481-012-9412-x
PMCID: PMC3690588  PMID: 23114888
Wnt signaling; β-catenin; Neurodegenerative diseases; T cell differentation; NeuroAIDS
8.  Inhibition of Tat-mediated HIV-1 replication and neurotoxicity by novel GSK3-beta inhibitors 
Virology  2011;415(1):56-68.
The HIV-1 protein Tat is a critical regulator of viral transcription and has also been implicated as a mediator of HIV-1 induced neurotoxicity. Here using a high throughput screening assay, we identified the GSK-3 inhibitor 6BIO, as a Tat-dependent HIV-1 transcriptional inhibitor. Its ability to inhibit HIV-1 transcription was confirmed in TZM-bl cells, with an IC50 of 40 nM. Through screening 6BIO derivatives, we identified 6BIOder, which has a lower IC50 of 4 nM in primary macrophages and 0.5 nM in astrocytes infected with HIV-1. 6BIOder displayed an IC50 value of 0.03 nM through in vitro GSK-3β kinase inhibition assays. Finally, we demonstrated 6BIO and 6BIOder have neuroprotective effects on Tat induced cell death in rat mixed hippocampal cultures. Therefore 6BIO and its derivatives are unique compounds which, due to their complex mechanisms of action, are able to inhibit HIV-1 transcription as well as to protect against Tat induced neurotoxicity.
doi:10.1016/j.virol.2011.03.025
PMCID: PMC3677548  PMID: 21514616
HIV-1; transcriptional inhibition; GSK-3; Tat; HAND; neuroprotection; indirubin; therapeutic target
9.  HIV-1 Tat through its intact core and cysteine-rich domains inhibits Wnt/β-catenin signaling in astrocytes: Relevance to HIV neuropathogenesis 
Wnt/β-catenin is a neuroprotective pathway regulating cell fate commitment in the CNS and many vital functions of neurons and glia. Its dysregulation is linked to a number of neurodegenerative diseases. Wnt/β-catenin is also a repressor of HIV transcription in multiple cell types, including astrocytes, which are dysregulated in HIV-associated neurocognitive disorder. Given that HIV proteins can overcome host restriction factors and that perturbations of Wnt/β-catenin signaling can compromise astrocyte function, we evaluated the impact of HIV transactivator of transcription (Tat) on Wnt/β-catenin signaling in astrocytes. HIV clade B Tat, in primary progenitor-derived astrocytes (PDAs) and U87MG cells, inhibited Wnt/β-catenin signaling as demonstrated by its inhibition of active β-catenin, TOPflash reporter activity, and Axin-2 (a downstream target of Wnt/β-catenin signaling). Point mutations in either the core region (K41A) or the cysteine-rich region (C30G) of Tat abrogated its ability to inhibit β-catenin signaling. Clade C Tat, which lacks the dicysteine motif, did not alter β-catenin signaling, confirming that the dicysteine motif is critical for Tat inhibition of β-catenin signaling. Tat co-precipitated with TCF-4 (a transcription factor that partners with β-catenin) suggesting a physical interaction between these two proteins. Further, knock down of β-catenin or TCF-4 enhanced docking of Tat at the TAR region of the HIV LTR. These findings highlight a bidirectional interference between Tat and Wnt/β-catenin that negatively impacts their cognate target genes. The consequences of this interaction include alleviation of Wnt/β-catenin mediated suppression of HIV and possible astrocyte dysregulation contributing to HIV neuropathogenesis.
doi:10.1523/JNEUROSCI.3145-12.2012
PMCID: PMC3508723  PMID: 23152614
10.  Identification of Novel T Cell Factor 4 (TCF-4) Binding Sites on the HIV Long Terminal Repeat Which Associate with TCF-4, β-Catenin, and SMAR1 To Repress HIV Transcription 
Journal of Virology  2012;86(17):9495-9503.
Molecular regulation of HIV transcription is a multifaceted process dictated in part by the abundance of cellular transcription factors that induce or repress HIV promoter activity. β-Catenin partners with members of the T cell factor (TCF)/LEF transcription factors to regulate gene expression. The interaction between β-catenin and TCF-4 is linked to inhibition of HIV replication in multiple cell types, including lymphocytes and astrocytes. Here, we evaluated the molecular mechanism by which β-catenin/TCF-4 repress HIV replication. We identified for the first time multiple TCF-4 binding sites at −336, −143, +66, and +186 relative to the transcription initiation site on the HIV long terminal repeat (LTR). Two of the sites (−143 and +66) were present in approximately 1/3 of 500 HIV-1 isolates examined. Although all four sites could bind to TCF-4, the strongest association occurred at −143. Deletion and/or mutation of −143, in conjunction with β-catenin or TCF-4 knockdown in cells stably expressing an LTR reporter construct, enhanced basal HIV promoter activity by 5-fold but had no effect on Tat-mediated transactivation of the HIV LTR. We also found that TCF-4, β-catenin, and the nuclear matrix binding protein SMAR1 tether at the −143-nucleotide (nt) site on the HIV LTR to inhibit HIV promoter activity. Collectively, these data indicate that TCF-4 and β-catenin at −143 associate with SMAR1, which likely pulls the HIV DNA segment into the nuclear matrix and away from transcriptional machinery, leading to repression of basal HIV LTR transcription. These studies point to novel avenues for regulation of HIV replication by manipulation of β-catenin signaling within cells.
doi:10.1128/JVI.00486-12
PMCID: PMC3416155  PMID: 22674979
11.  NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses 
Nature medicine  2012;18(3):422-428.
CD4-unhelped CD8+ T cells are functionally-defective cells primed in the absence of CD4+ T cell help and present a critical problem. Based on the co-stimulatory and non-canonical roles of NKG2D on CD8+ T cells, we investigated its ability to rescue these immunologically-impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, responses. NKG2D-mediated rescue is characterized by reversal of elevated T-bet expression and recovery of IL-2 and IFN-γ production and cytolytic responses. Rescue is abrogated in CD8+ T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4+ T cells in a CD4-dependent influenza model and rescues HIV-specific CD8+ T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8+ T cells from their pathophysiological fate and may provide therapeutic benefits.
doi:10.1038/nm.2683
PMCID: PMC3436127  PMID: 22366950
12.  Role of β-Catenin and TCF/LEF Family Members in Transcriptional Activity of HIV in Astrocytes 
Journal of Virology  2012;86(4):1911-1921.
The Wnt/β-catenin pathway is involved in diverse cell functions governing development and disease. β-Catenin, a central mediator of this pathway, binds to members of the TCF/LEF family of transcription factors to modulate hundreds of genes. Active Wnt/β-catenin/TCF-4 signaling plays a significant role in repression of HIV-1 replication in multiple cell targets, including astrocytes. To determine the mechanism by which active β-catenin/TCF-4 leads to inhibition of HIV replication, we knocked down β-catenin or TCF/LEF members in primary astrocytes and astrocytomas transiently transfected with an HIV long terminal repeat (LTR)-luciferase reporter that contained an integrated copy of the HIV LTR-luciferase construct. Knockdown of either β-catenin or TCF-4 induced LTR activity by 2- to 3-fold under both the episomal and integrated conditions. This knockdown also increased presence of serine 2-phosphorylated RNA polymerase II (Pol II) on the HIV LTR as well as enhanced its processivity. Knockdown of β-catenin/TCF-4 also impacted tethering of other transcription factors on the HIV promoter. Specifically, knockdown of TCF-4 enhanced binding of C/EBPβ, C/EBPδ, and NF-κB to the HIV LTR, while β-catenin knockdown increased binding of C/EBPβ and C/EBPδ but had no effect on NF-κB. Approximately 150 genes in astrocytes were impacted by β-catenin knockdown, including genes involved in inflammation/immunity, uptake/transport, vesicular transport/exocytosis, apoptosis/cellular stress, and cytoskeleton/trafficking. These findings indicate that modulation of the β-catenin/TCF-4 axis impacts the basal level of HIV transcription in astrocytes, which may drive low level/persistent HIV in astrocytes that can contribute to ongoing neuroinflammation, and this axis also has profound effects on astrocyte biology.
doi:10.1128/JVI.06266-11
PMCID: PMC3302377  PMID: 22156527
13.  IFN-γ Mediates Enhancement of HIV Replication in Astrocytes by Inducing an Antagonist of the β-Catenin Pathway (DKK1) in a STAT 3-Dependent Manner 
Typically, IFN-γ is an antiviral cytokine that inhibits the replication of many viruses, including HIV. However, in the CNS, IFN-γ induces HIV-productive replication in astrocytes. Although astrocytes in vitro are refractory to HIV replication, recent in vivo evidence demonstrated that astrocytes are infected by HIV, and their degree of infection is correlated with proximity to activated macrophages/microglia. The ability of IFN-γ to induce HIV replication in astrocytes suggests that the environmental milieu is critical in regulating the permissiveness of astrocytes to HIV infection. We evaluated the mechanism by which IFN-γ relieves restricted HIV replication in astrocytes. We demonstrate that although astrocytes have robust endogenous β-catenin signaling, a pathway that is a potent inhibitor of HIV replication, IFN-γ diminished β-catenin signaling in astrocytes by 40%, as evaluated by both active β-catenin protein expression and β-catenin-mediated T cell factor/lymphoid enhancer reporter (TOPflash) activity. Further, IFN-γ–mediated inhibition of β-catenin signaling was dependent on its ability to induce an antagonist of the β-catenin signaling pathway, Dickkopf-related protein 1, in a STAT 3-dependent manner. Inhibition of STAT3 and Dickkopf-related protein 1 abrogated the ability of IFN-γ to enhance HIV replication in astrocytes. These data demonstrated that IFN-γ induces HIV replication in astrocytes by antagonizing the β-catenin pathway. To our knowledge, this is the first report to point to an intricate cross-talk between IFN-γ signaling and β-catenin signaling that may have biologic and virologic effects on HIV outcome in the CNS, as well as on broader processes where the two pathways interface.
doi:10.4049/jimmunol.1100099
PMCID: PMC3167069  PMID: 21562161
14.  Negative-Strand Hepatitis C Virus (HCV) RNA in Peripheral Blood Mononuclear Cells from Anti-HCV–Positive/HIV-Infected Women 
The Journal of Infectious Diseases  2006;195(1):124-133.
Background
Hepatitis C virus (HCV) has been reported to replicate in peripheral blood mononuclear cells (PBMCs), particularly in patients coinfected with HCV and human immunodeficiency virus (HIV). However, there are limited data regarding the prevalence of and the factors associated with extrahepatic replication.
Methods
The presence of negative-strand HCV RNA in PBMCs was evaluated by a strand-specific assay for 144 anti-HCV–positive/HIV-infected women enrolled in the Women’s Interagency HIV Study. One to 5 PBMC samples obtained from each woman were tested. Multivariate analyses were used to assess for associations with the clinical and demographic characteristics of the women.
Results
Negative-strand HCV RNA was detected in 78 (25%) of 315 specimens, and, for 61 women (42%), ≥1 specimen was found to have positive results. The presence of negative-strand HCV RNA in PBMCs was significantly positively associated with an HCV RNA plasma level of ≥6.75 log copies/mL (P =.04) and consumption of ≥7 alcoholic drinks per week (P =.02). It was also negatively associated with injection drug use occurring in the past 6 months (P =.03). A negative association with a CD4+CD38+DR+ cell percentage of >10% and a positive association with acquired immunodeficiency syndrome were borderline significant (P =.05).
Conclusions
HCV replication in PBMCs is common among HIV-coinfected women and appears to be a dynamic process related to lifestyle, virologic, and immunologic factors.
doi:10.1086/509897
PMCID: PMC3319123  PMID: 17152016
15.  Human FasL Gene Is a Target of β-Catenin/T-Cell Factor Pathway and Complex FasL Haplotypes Alter Promoter Functions 
PLoS ONE  2011;6(10):e26143.
FasL expression on human immune cells and cancer cells plays important roles in immune homeostasis and in cancer development. Our previous study suggests that polymorphisms in the FasL promoter can significantly affect the gene expression in human cells. In addition to the functional FasL SNP -844C>T (rs763110), three other SNPs (SNP -756A>G or rs2021837, SNP -478A>T or rs41309790, and SNP -205 C>G or rs74124371) exist in the proximal FasL promoter. In the current study, we established three major FasL hyplotypes in humans. Interestingly, a transcription motif search revealed that the FasL promoter possessed two consensus T-cell factor (TCF/LEF1) binding elements (TBEs), which is either polymorphic (SNP -205C>G) or close to the functional SNP -844C>T. Subsequently, we demonstrate that both FasL TBEs formed complexes with the TCF-4 and β-catenin transcription factors in vitro and in vivo. Co-transfection of LEF-1 and β-catenin transcription factors significantly increased FasL promoter activities, suggesting that FasL is a target gene of the β-catenin/T-cell factor pathway. More importantly, we found that the rare allele (-205G) of the polymorphic FasL TBE (SNP -205C>G) failed to bind the TCF-4 transcription factor and that SNP -205 C>G significantly affected the promoter activity. Furthermore, promoter reporter assays revealed that FasL SNP haplotypes influenced promoter activities in human colon cancer cells and in human T cells. Finally, β-catenin knockdown significantly decreased the FasL expression in human SW480 colon cancer cells. Collectively, our data suggest that β-catenin may be involved in FasL gene regulation and that FasL expression is influenced by FasL SNP haplotypes, which may have significant implications in immune response and tumorigenesis.
doi:10.1371/journal.pone.0026143
PMCID: PMC3191176  PMID: 22022540
16.  Evaluating the Impact of Hepatitis C Virus (HCV) on Highly Active Antiretroviral Therapy–Mediated Immune Responses in HCV/HIV-Coinfected Women: Role of HCV on Expression of Primed/Memory T Cells 
The Journal of infectious diseases  2006;193(9):1202-1210.
Objective
To evaluate the impact of hepatitis C virus (HCV) on the immune system before receipt of highly active antiretroviral therapy (HAART) and on immune recovery after receipt of HAART among human immunodeficiency virus (HIV)/HCV–coinfected women enrolled in the Women’s Interagency HIV Study.
Methods
The study included 294 HIV-infected women who initiated HAART and attended 2 follow-up visits. The women were grouped on the basis of positive HCV antibody and HCV RNA tests. There were 148 women who were HCV antibody negative, 34 who were HCV antibody positive but RNA negative, and 112 who were HCV antibody and RNA positive. Immune recovery was measured by flow-cytometric assessment for markers of activation and maturation on CD4+ and CD8+ T cells. Data analysis used repeated measures of variance.
Results
HIV/HCV coinfection is associated with an increased number of CD4+ and CD8+ primed/memory T cells. HIV/HCV coinfection, however, did not affect any further decreases in CD4+ or CD4+ and CD8+ naive/memory T cell counts or enhanced T cell activation. HIV/HCV coinfection also did not affect HAART responses in the CD4+ and CD8+ T cell compartment.
Conclusions
HCV does not affect immune responses to HAART in HIV/HCV–coinfected individuals but is associated with an expansion of CD4+ and CD8+ memory T cell subsets. Functional impairment in the CD4+ and CD8+ T cell compartments still needs to be assessed in coinfected patients.
doi:10.1086/500843
PMCID: PMC3126663  PMID: 16586355
17.  Activation of CD8 T Cells Predicts Progression of HIV Infection in Women Coinfected with Hepatitis C Virus 
The Journal of infectious diseases  2010;201(6):823-834.
Background
Because activation of T cells is associated with human immunodeficiency virus (HIV) pathogenesis, CD4 and CD8 activation levels in patients coinfected with HIV and hepatitis C virus (HCV) may explain conflicting reports regarding effects of HCV on HIV disease progression.
Methods
Kaplan-Meier and multivariate Cox regression models were used to study the risk of incident clinical AIDS and AIDS-related deaths among 813 HCV-negative women with HIV infection, 87 HCV-positive nonviremic women with HIV coinfection, and 407 HCV-positive viremic women with HIV coinfection (median follow-up time, 5.2 years). For 592 women, the percentages of activated CD4 and CD8 T cells expressing HLA-DR (DR) and/or CD38 were evaluated.
Results
HCV-positive viremic women had a statistically significantly higher percentage of activated CD8 T cells (P < .001) and a statistically significantly higher incidence of AIDS compared with HCV-negative women (P < .001 [log-rank test]). The AIDS risk was greater among HCV-positive viremic women in the highest tertile compared with the lowest tertile (>43% vs <26%) of CD8+CD38+DR+ T cells (hazard ratio, 2.94 [95% confidence interval, 1.50–5.77]; P =.001). This difference was not observed in the HCV-negative women (hazard ratio, 1.87 [95% confidence interval, 0.80–4.35]; P =.16). In contrast, CD4 activation predicted AIDS in both groups similarly. Increased percentages of CD8+CD38−DR+, CD4+CD38−DR−, and CD8+CD38−DR− T cells were associated with a >60% decreased risk of AIDS for HCV-positive viremic women and HCV-negative women.
Conclusion
HCV-positive viremic women with HIV coinfection who have high levels of T cell activation may have increased risk of AIDS. Earlier treatment of HIV and HCV infection may be beneficial.
doi:10.1086/650997
PMCID: PMC3105602  PMID: 20151840
18.  Immunophenotypic Alterations in Acute and Early HIV Infection 
Clinical immunology (Orlando, Fla.)  2007;125(3):299-308.
To understand the extent of immune dysregulation in primary HIV infection (PHI) and the impact of antiretroviral therapy (ART) on restoring these abnormalities, we longitudinally evaluated 52 subjects {Acute Treated (AT); Early Treated (ET); Early Untreated (EU)) for markers of activation, proliferation, and function on T cells. ET and AT patients differed by 0.54 log viral load (VL) at baseline but did not differ thereafter by more than 0.34 log10 VL. AT subjects had higher CD8+ T cell counts and expression of markers indicative of CD8+ T cell activation (CD38), and proliferation (Ki67), at baseline, than ET subjects but were not different post-48 weeks of ART. Although acute PHI is marked by higher level of immune activation than early PHI, virologic and immunologic responses were similar post-ART, suggesting that the extent of immunologic recovery is not negatively impacted by a delay of treatment beyond the acute stage of disease.
doi:10.1016/j.clim.2007.08.011
PMCID: PMC2702986  PMID: 17916441
Primary HIV infection; Early HIV; Acute HIV; Immune reconstitution; Immunophenotyping
19.  CD8+ T Cell Activation in Women Coinfected with Human Immunodeficiency Virus Type 1 and Hepatitis C Virus 
The Journal of infectious diseases  2008;197(10):1402-1407.
Immune activation is a hallmark of human immunodeficiency virus type 1 (HIV-1) infection and impacts innate and adaptive immunity. Individuals coinfected with HIV-1 and hepatitis C virus (HCV) may have increased immune activation early in HIV disease because of a high HCV antigen load in tissues such as the liver. We evaluated T cell markers of activation and maturation in women with or without HIV-1 infection, by HCV antibody and HCV RNA status. We found increased percentages of activated CD8+ T cells (i.e., CD8+HLA-DR+38+ cells and CD8+CD28+HLA-DR+ cells) but not of CD4+ T cells among women who tested positive for HIV-1, HCV antibody, and HCV RNA, compared with HIV-1–positive women who tested negative for HCV antibody. Because CD8+T cell activation is related to HIV-1 disease progression, these data may have implications for the medical management of patients coinfected with HIV-1 and HCV.
doi:10.1086/587696
PMCID: PMC2443164  PMID: 18444798
20.  Active β-Catenin Signaling Is an Inhibitory Pathway for Human Immunodeficiency Virus Replication in Peripheral Blood Mononuclear Cells▿  
Journal of Virology  2008;82(6):2813-2820.
The Wnt/β-catenin pathway is involved in cell functions governing development and disease. In modeling postentry restriction of human immunodeficiency virus (HIV) replication in astrocytes, we reported that part of this natural resistance to productive replication of HIV in astrocytes involved expression of proteins of the Wnt/β-catenin signaling pathway. We determined here whether induction of β-catenin signaling in peripheral blood mononuclear cells (PBMCs) can modulate HIV replication. Given that lithium is an inducer of β-catenin signaling, we used it as a tool to determine the impact of β-catenin signaling on HIV replication in PBMCs. We demonstrated that lithium inhibited the replication of T-tropic and primary isolates of HIV by >90% and did so in noncytotoxic/noncytostatic concentrations and in a β-catenin-dependent manner. Specifically, inhibiting β-catenin signaling by transfection of dominant-negative mutant constructs to either T-cell factor 4, the downstream effector of Wnt signaling, or β-catenin, the central mediator of this pathway, abrogated the ability of lithium to inhibit HIV replication. Moreover, when Wnt/β-catenin signaling was inhibited, the level of HIV replication was enhanced by fourfold. To confirm the in vivo relevance of the β-catenin pathway in repressing HIV replication, we evaluated HIV-positive antiretroviral therapy-naive patients who were on lithium therapy. These patients demonstrated a reduction in viral load, which increased as the dose of lithium was reduced. Collectively, these data indicate that β-catenin signaling is an intrinsic molecular pathway restricting HIV replication in PBMCs.
doi:10.1128/JVI.02498-07
PMCID: PMC2258975  PMID: 18199649
21.  Human Immunodeficiency Virus-Restricted Replication in Astrocytes and the Ability of Gamma Interferon To Modulate This Restriction Are Regulated by a Downstream Effector of the Wnt Signaling Pathway▿  
Journal of Virology  2007;81(11):5864-5871.
Astrocyte dysregulation correlates with the severity and the rate of human immunodeficiency virus (HIV)-associated dementia (HAD) progression, highlighting a pivotal role for astrocytes in HIV neuropathogenesis. Yet, astrocytes limit HIV, indicating that they posses an intrinsic molecular mechanism to restrict HIV replication. We previously established that this restriction can be partly overcome by priming astrocytes with gamma interferon (IFN-γ), which is elevated in the cerebral spinal fluid of HAD patients. We evaluated the mechanism of restrictive HIV replication in astrocytes and how IFN-γ priming modulates this restriction. We demonstrate that the downstream effector of Wnt signaling, T-cell factor 4 (TCF-4), is part of a transcriptional complex that is immunoprecipitated with HIV TAR-containing region in untreated astrocytes but not in IFN-γ-treated cells. Blocking TCF-4 activity with a dominant-negative mutant enhanced HIV replication by threefold in both the astrocytoma cell line U87MG and primary fetal astrocytes. Using a TCF-4 reporter plasmid, we directly demonstrate that Wnt signaling is active in human astrocytes and is markedly reduced by IFN-γ treatment. Collectively, these data implicate TCF-4 in repressing HIV replication and the ability of IFN-γ to regulate this restriction by inhibiting TCF-4. Given that TCF-4 is the downstream effector of Wnt signaling, harnessing Wnt signaling as an intrinsic molecular mechanism to limit HIV replication may emerge as a powerful tool to regulate HIV replication within and outside of the brain.
doi:10.1128/JVI.02234-06
PMCID: PMC1900315  PMID: 17392368
22.  Gamma Interferon Primes Productive Human Immunodeficiency Virus Infection in Astrocytes 
Journal of Virology  2006;80(1):541-544.
Considerable controversy exists over whether astrocytes can support human immunodeficiency virus (HIV) infection. We evaluated the impact of three cytokines critical to the development of HIV neuropathogenesis, gamma interferon (IFN-γ), granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha, on priming astrocytes for HIV infection. We demonstrate that IFN-γ was the most potent in its ability to facilitate substantial productive HIV infection of an astroglioma cell line (U87MG) and human fetal astrocytes (HFA). The mechanism of IFN-γ-mediated priming of HIV in HFA is unlikely to be at the level of up-regulation of receptors and coreceptors relevant to HIV entry. These data demonstrate that cytokine priming can alter HIV replication in astrocytes.
doi:10.1128/JVI.80.1.541-544.2006
PMCID: PMC1317538  PMID: 16352578

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