Effect of Lithium in Murine Immunodeficiency Virus Infected Animals

Gallicchio, Vincent S.; Cibull, Michael L.; Hughes, Nedda K.; Tse, Kam-Fai

doi:10.1159/000163797

Cited by 20 publications

(18 citation statements)

References 24 publications

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“…Toxicities and most side effects can be managed by initial and periodic monitoring of lithium serum levels and monitoring of thyroid and renal functions. Several animal and human studies further suggest a benefit of lithium administration in neuroprotection in HIV (5,6,18,20) and in Alzheimer's disease (23). Specifically, lithium prevents gp120-and Tat-induced HIV neurodegeneration in vitro (5,20) and increases soluble TNF-␣ receptor, which absorbs the neurotoxic TNF-␣ cytokine (11).…”

Section: Discussionmentioning

confidence: 99%

Active β-Catenin Signaling Is an Inhibitory Pathway for Human Immunodeficiency Virus Replication in Peripheral Blood Mononuclear Cells

Kumar

Zloza

Moon

et al. 2008

J Virol

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The Wnt/␤-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/␤-catenin signaling pathway. We determined here whether induction of ␤-catenin signaling in peripheral blood mononuclear cells (PBMCs) can modulate HIV replication. Given that lithium is an inducer of ␤-catenin signaling, we used it as a tool to determine the impact of ␤-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 ␤-catenin-dependent manner. Specifically, inhibiting ␤-catenin signaling by transfection of dominant-negative mutant constructs to either T-cell factor 4, the downstream effector of Wnt signaling, or ␤-catenin, the central mediator of this pathway, abrogated the ability of lithium to inhibit HIV replication. Moreover, when Wnt/␤-catenin signaling was inhibited, the level of HIV replication was enhanced by fourfold. To confirm the in vivo relevance of the ␤-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 ␤-catenin signaling is an intrinsic molecular pathway restricting HIV replication in PBMCs.

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Section: Discussionmentioning

confidence: 99%

Active β-Catenin Signaling Is an Inhibitory Pathway for Human Immunodeficiency Virus Replication in Peripheral Blood Mononuclear Cells

Kumar

Zloza

Moon

et al. 2008

J Virol

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“…In a mouse model of neuroAIDS, LiCl was able to restore loss of microtubule-associated protein-2 + neurites and synaptic density that is often observed with HIV invasion of the CNS (38). Lithium remarkably improved neurocognition in HIV + patients in a small clinical trial (39). Our previous studies defined an antiviral effect of LiCl that is β-catenin pathway dependent (39–41).…”

Section: Discussionmentioning

confidence: 99%

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

Henderson

Major

et al. 2011

The Journal of Immunology

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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.

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“…In particular, interest has recently developed for three psychiatric medications -valproic acid (VPA) (Ances et al, 2006, Schifitto et al, 2006, serotonin reuptake inhibitors (SRIs) , and lithium (Gallicchio, Cibull, Hughes, & Tse, 1993;Harvey, Meyer, Gallichio, & Manji, 2002;Dou et al, 2005;Letendre et al, 2006). Both VPA and lithium are inhibitors of glycogen synthase kinase-3 beta (GSK-3) (REF the Richman paper) and may therefore lead to an overall reduction in HIV RNA levels while the mechanism for the impact of SRIs on HIV replication remains relatively unknown (Kristiansen & Hansen, 2000).…”

Section: Introductionmentioning

confidence: 99%

Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders

Ances

Letendre

Alexander

et al. 2008

International Review of Psychiatry

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Effective combination antiretroviral therapies (ART) have markedly lengthened survival among HIV infected individuals. In this long-surviving cohort, both psychiatric comorbidities and HIV-associated neurocognitive disorders (HAND) remain common. Even mild neurocognitive impairment can significantly disrupt of activities of daily living and reduce quality of life. Persistence of HAND might reflect incomplete containment of HIV within the central nervous system (CNS) due to the limited penetration of most antiretrovirals (ARVs) across the blood-brain barrier. Recent data support that certain medications used to treat psychiatric comorbidities in HIV-infected individuals may also protect the brain from toxic byproducts of HIV replication and neuroinflammation. Two drug classes in particular, glycogen synthase kinase-3 beta (GSK-3b) inhibitors and serotonin reuptake inhibitors (SRIs), may benefit individuals with HAND. Valproic acid (VPA) and lithium are potentially beneficial GSK-3b inhibitors. While the mechanism of benefit of SRIs in HAND remains unknown, evidence supports some benefit of citalopram and paroxetine. The present brief review focuses on these drugs and assesses their possible adjunct roles in the treatment of HIV-infected individuals.

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Effect of Lithium in Murine Immunodeficiency Virus Infected Animals

Cited by 20 publications

References 24 publications

Active β-Catenin Signaling Is an Inhibitory Pathway for Human Immunodeficiency Virus Replication in Peripheral Blood Mononuclear Cells

Active β-Catenin Signaling Is an Inhibitory Pathway for Human Immunodeficiency Virus Replication in Peripheral Blood Mononuclear Cells

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

Role of psychiatric medications as adjunct therapy in the treatment of HIV associated neurocognitive disorders

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