scholarly journals Correction to: Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders

2021 ◽  
Author(s):  
Michael T. Nedelcovych ◽  
Boe-Hyun Kim ◽  
Xiaolei Zhu ◽  
Lyndah E. Lovell ◽  
Arena A. Manning ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Murine Model ◽  
Neurocognitive Disorders ◽  
Glutamate Production ◽  
Hiv Associated Neurocognitive Disorders

scholarly journals HIV associated neurocognitive disorders

2013 ◽  
Vol 5 (1S) ◽  
pp. 8 ◽  
Author(s):  
Li Zhou ◽  
Nitin K. Saksena
Keyword(s):  
Cognitive Deficits ◽  
Highly Active Antiretroviral Therapy ◽  
Neurocognitive Disorders ◽  
Future Research ◽  
Clear Understanding ◽  
Motor Impairments ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv Associated Neurocognitive Disorders

Human immunodeficiency virus type 1 is associated with the development of neurocognitive disorders in many infected individuals, including a broad spectrum of motor impairments and cognitive deficits. Despite extensive research, the pathogenesis of HIV-associated neurocognitive disorders (HAND) is still not clear. This review provides a comprehensive view of HAND, including HIV neuroinvasion, HAND diagnosis and different level of disturbances, influence of highly-active antiretroviral therapy to HIV-associated dementia (HAD), possible pathogenesis of HAD, etc. Together, this review will give a thorough and clear understanding of HAND, especially HAD, which will be vital for future research, diagnosis and treatment.

scholarly journals Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Christina Gavegnano ◽  
Woldeab B. Haile ◽  
Selwyn Hurwitz ◽  
Sijia Tao ◽  
Yong Jiang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Neurocognitive Disorders ◽  
Lymphoid Cells ◽  
High Dose ◽  
Jak Inhibitors ◽  
Hiv Encephalitis ◽  
Cns Inflammation ◽  
Human Macrophages ◽  
Hiv Associated Neurocognitive Disorders

Abstract Background Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines. Methods Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. Results In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. Conclusion These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.

scholarly journals Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

2015 ◽  
Vol 89 (20) ◽  
pp. 10656-10667 ◽  
Author(s):  
Alexander J. Gill ◽  
Colleen E. Kovacsics ◽  
Patricia J. Vance ◽  
Ronald G. Collman ◽  
Dennis L. Kolson
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Heme Oxygenase ◽  
Neurocognitive Disorders ◽  
Heme Oxygenase 1 ◽  
Type I ◽  
Hiv Replication ◽  
Glutamate Production ◽  
Hiv 1 ◽  
Hiv Associated Neurocognitive Disorders

ABSTRACTExpression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIV-positive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses.In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genesnef,vpr, orvpubut rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIV-infected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis.IMPORTANCEThe continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART.

Youth perinatal HIV-associated neurocognitive disorders: association with functional impairment

AIDS Care ◽  
2021 ◽  
pp. 1-5
Author(s):  
Nicole Phillips ◽  
Kevin G. F. Thomas ◽  
Bulelwa Mtukushe ◽  
Landon Myer ◽  
Heather J. Zar ◽  
...  
Keyword(s):  
Functional Impairment ◽  
Neurocognitive Disorders ◽  
Perinatal Hiv ◽  
Hiv Associated Neurocognitive Disorders
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