Bile pigments as HIV-1 protease inhibitors and their effects on HIV-1 viral maturation and infectivity <i>in vitro</i>

McPhee, Fiona; Caldera, P.; Bemis, Guy W.; McDonagh, Antony F.; Kuntz, Irwin D.; Craik, Charles S.

doi:10.1042/bj3200681

Cited by 63 publications

(40 citation statements)

References 46 publications

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“…The important issues concerning the availability of haem as a substrate for augmented HO-1 levels and the generation of bilirubin in sufficient amounts to provide resistance to stressful stimuli were also raised. The present findings strongly support a role for bilirubin derived from HO-1 in cytoprotection ; nevertheless, the participation of the other products of haem degradation by HO-1 is attainable since CO, biliverdin and iron have all been shown to modulate biological processes [12,13,[26][27][28]. Accordingly, Otterbein and co-workers have reported recently that exposure of rats to low concentrations of CO increases tolerance to hyperoxic lung injury [29].…”

Section: Figure 4 Effect Of Exogenous Bilirubin On Gox-mediated Cell supporting

confidence: 72%

Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

Clark

Foresti

Green

et al. 2000

Biochemical Journal

219

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The inducible isoform of haem oxygenase (HO-1) has been proposed as an effective system to counteract oxidant-induced cell injury. In several circumstances, this cytoprotective effect has been attributed to increased generation of the antioxidant bilirubin during haem degradation by HO-1. However, a direct implication for HO-1-derived bilirubin in protection against oxidative stress remains to be established. In the present study, we examined the dynamics of HO-1 expression and bilirubin production after stimulation of vascular smooth-muscle cells with hemin, a potent inducer of the HO-1 gene. We found that hemin-mediated increase in HO-1 protein expression and haem oxygenase activity is associated with augmented bilirubin levels. The majority of bilirubin production occurred early after exposure of cells to hemin. Hemin pre-treatment also resulted in high resistance to cell injury caused by an oxidant-generating system. Interestingly, this protective effect was manifest only when cells were actively producing bilirubin as a consequence of increased haem availability and utilization by HO-1. Tin protoporphyrin IX, an inhibitor of haem oxygenase activity, significantly reduced bilirubin generation and reversed cellular protection afforded by hemin treatment. Furthermore, addition of bilirubin to the culture medium markedly reduced the cytotoxicity produced by oxidants. Our findings provide direct evidence that bilirubin generated after up-regulation of the HO-1 pathway is cytoprotective against oxidative stress.

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Section: Figure 4 Effect Of Exogenous Bilirubin On Gox-mediated Cell supporting

confidence: 72%

Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

Clark

Foresti

Green

et al. 2000

Biochemical Journal

219

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“…Thus, HO-1 might promote an interferon-mediated antiviral state. Other proposed HO-1 antiviral effects include posttranscriptional destabilization of viral core proteins, as for HBV (37), and inhibition of viral enzymes, as for the HIV protease by biliverdin and bilirubin (49). 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).…”

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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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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“…Indeed, strong negative associations have been observed between bilirubin level and incidence of cancer and cardiovascular disease (Novotny & Vitek, 2003;Zucker et al, 2004;Temme et al, 2001). Raised bilirubin levels can also inhibit replication in vitro of various blood pathogens including pneumococcus, the malaria parasite Plasmodium, and human immunodeficiency virus (HIV) (Najib, 1937;McPhee et al, 1996;Kumar et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Horsfall

Zeitlyn

Tarekegn

et al. 2011

Annals of Human Genetics

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SummaryVariation of a short (TA) n repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDPglucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA) 7 and (TA) 8 )) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA) n alleles frequencies were highest in equatorial Africa, (TA) 7, being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA) n . Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA) n on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.

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Bile pigments as HIV-1 protease inhibitors and their effects on HIV-1 viral maturation and infectivity in vitro

Cited by 63 publications

References 46 publications

Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

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

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

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