Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction

Devadas, Krishnakumar; Hewlett, Indira; Dhawan, Subhash

doi:10.1189/jlb.0307172

Cited by 29 publications

(30 citation statements)

References 69 publications

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“…The consistent ability of HIV to decrease HO-1 expression in macrophages suggests an adaptive benefit for the virus; however, the HIV-mediated loss of HO-1 in MDM seems unlikely to have a significant effect on HIV replication, as HO-1 deficiency is not observed until 6 to 9 days postinfection, after robust infection is established (3). Although induction of HO-1 in macrophages prior to HIV infection has been reported to reduce subsequent HIV replication, enzymatic inhibition of target cell HO-1 prior to infection does not augment subsequent HIV replication (35). Moreover, we demonstrated that potent HO-1 knockdown, HO-1 enzymatic inhibition, or induction of HO-1 expression in macrophages in which productive HIV replication is established does not alter replication (3).…”

Section: Discussionmentioning

confidence: 95%

“…Induction of HO-1 expression in uninfected macrophages has been shown to reduce subsequent HIV-1 infection and replication (34,35). An antiviral effect of HO-1 induction has been observed in infection studies of hepatitis C virus (HCV) (36), hepatitis B virus (HBV) (37), Ebola virus (38), enterovirus 71 (EV71) (39), vaccinia virus (40), and porcine reproductive and respiratory syndrome virus (41).…”

Section: Discussionmentioning

confidence: 99%

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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

Gill

Kovacsics

Vance

et al. 2015

J Virol

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Expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIVpositive 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 genes nef, vpr, or vpu but 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 HIVinfected 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. H eme oxygenase-1 (HO-1) is a highly inducible phase II d...

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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

Gill

Kovacsics

Vance

et al. 2015

J Virol

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“…27 Suppression of HIV-1 by haemin was reversed by protoporphyrin, an HO-1 inhibitor. 28 (2) Hypoxia related to anaemia and vaso-occlusive episodes may contribute to inhibition of HIV. 29e31 Our previous molecular studies showed that HIV-1 transcription is inhibited in cells cultured under lower oxygen conditions.…”

Section: Discussionmentioning

confidence: 99%

Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in US hospital discharge records: a cross-sectional study

Nouraie¹,

Nekhai

2012

Sex Transm Infect

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Objective Some studies suggest that HIV infection progresses slowly in patients with sickle cell disease (SCD). The authors aimed to determine the relationships between SCD and HIV infection. Methods National Hospital Discharge Survey data from adult Africane–Americans in the period of 1997–2009 were analysed. The comorbidities of SCD with HIV infections in hospital discharges were analysed. Multiple logistic regression was used to test the association between SCD and HIV. For comparative purposes, the relationships of SCD with hepatitis B virus (HBV) and hepatitis C virus (HCV) were also assessed. Results 423 431 records were divided into two time periods 1997–2003 (53% of records) and 2004–2009 (47% of records). The frequency of HIV diagnosis was lower in patients with SCD (1.5% vs 3.3% in patients without SCD). In logistic regression, SCD diagnosis was associated with an OR of 0.24 (95% CI 0.18 to 0.32) for HIV diagnosis in the first period and with an OR of 0.31 (95% CI 0.22 to 0.42) in the second period. In contrast, SCD was associated with higher risk of HCV (OR=2.01, 95% CI 1.56 to 2.59 in the first period and OR=2.12, 95% CI 1.71 to 2.63 in the second period). SCD was also associated with a higher risk of HBV (OR=1.15, 95% CI 0.72 to 1.83 in the first period and OR=1.82, 95% CI 1.24 to 2.68 in the second period). Conclusions The lower risk of HIV comorbidity, but not HCV and HBV, with SCD is consistent with the possibility that SCD has a unique effect in altering the risk of HIV infection or progression. Investigation of how the haemolytic and immunological changes of SCD influence HIV might lead to new therapeutic or preventive approaches.

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“…The alpha7 nicotinic acetylcholine receptor [233] and the beta adrenergic receptor in RAW 264.7 macrophage cell lines [234] are also reported to initiate HO-1 expression, either through protein kinase C (PKC) or protein kinase A (PKA), respectively. Some reports state the HO-1 expression is signaled via PKC activity [183, 235], while others report extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)-mediated induction [236, 237], and perhaps activation of both PKC and ERK [238]. ERK may also regulate HO-1 production at the translational level rather than at the transcriptional level [239].…”

Section: Signaling Pathways Of Heme Oxygenase-1 Expressionmentioning

confidence: 99%

Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders

Ambegaokar¹,

Kolson

2014

CHR

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Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that subserves cytoprotective responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, HO-1 expression is increased, presumably reflecting an endogenous neuroprotective response against ongoing cellular injury. In contrast, we have found that in human immunodeficiency virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress and neurodegeneration, HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways activated by HIV infection. We have also shown that HO-1 expression is significantly suppressed by HIV replication in cultured macrophages which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this glutamate-mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages. Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in macrophages, which could promote neuronal survival through HO-1-modulation of endogenous antioxidant and immune modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV infection is also discussed.

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Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction

Cited by 29 publications

References 69 publications

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

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

Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in US hospital discharge records: a cross-sectional study

Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders

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