Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

Calcagno, Andrea; Perri, Giovanni Di; Bonora, Stefano

doi:10.1007/s40262-014-0171-0

Cited by 59 publications

(60 citation statements)

References 179 publications

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“…Each regimen included the two nucleoside reverse transcriptase inhibitors (NRTIs), tenofovir disoproxil fumarate (TDF; 20 nM) and emtricitabine (FTC; 500 nM), in addition to (i) efavirenz (EFZ; 40 nM), a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen (regimen 1); (ii) atazanavir boosted with ritonavir (ATV/r; 15 nM/10 nM), a protease inhibitor (PI)-based regimen (regimen 2); or (iii) raltegravir (RAL; 50 nM), an integrase strand transfer inhibitor (INSTI)-based regimen (regimen 3). The chosen drug concentrations were based upon reported cerebrospinal fluid drug concentrations in ART-treated patients (30). To more effectively suppress HIV replication, we also used a high-dose PI-based regimen with 5-foldhigher ATV/r concentrations (75 nM/50 nM) and unchanged TDF and FTC concentrations (regimen 4).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…These infected cells are broadly disseminated across numerous tissues, including sites that may be relatively inaccessible to host defenses or treatment strategies, such as the lymphatic tissue and the central nervous system, where concentrations of antiviral drugs are lower than in peripheral blood (2,3). HIV can spread through cell-to-cell transmission in the presence of antiretroviral therapy (ART) concentrations that effectively inhibit extra-cellular viral infection of susceptible cells (4).…”

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confidence: 99%

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication

Campbell

Bruckman

Herns

et al. 2018

Journal of Biological Chemistry

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“…Moreover, we have to consider that the drugs concentrations used in our experiments, even if chosen based on previously reported literature data, could not precisely reflect the administration conditions in newborns [15,16]. Nevertheless it should be said that HIV protease inhibitors have poor penetration into the cerebrospinal fluid (CSF) [22]; on the other hand, the blood brain barrier (BBB) in the embryo, foetus, and newborn is immature and thus fragile, making the developing brain more vulnerable to drugs [23]; furthermore, in many cases of HIV infection the infiltration of infected macrophages and lymphocytes into the brain across the vascular boundary perturbs the BBB, therefore, the ability to cross the physiological BBB is not necessarily correlated with the administered amount of drugs in the CNS [24].…”

Section: Discussionmentioning

confidence: 99%

HIV Protease Inhibitors Apoptotic Effect in SH-SY5Y Neuronal Cell Line

Tricarico

França

Pacor

et al. 2016

Cell Physiol Biochem

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Background: Prophylactic treatment regimens to prevent mother-to-child HIV transmission include protease inhibitors Lopinavir and Ritonavir. Lopinavir and Ritonavir have been reported to be able to induce intracellular oxidative stress in diverse cellular models, however scarce informations are available about protease inhibitor effects of in the central nervous system (CNS). In our study we evaluated the impact of protease inhibitors on a cell neuronal model. Methods: We treated a neuroblastoma cell line (SH-SY5Y) with increasing doses of Lopinavir and Ritonavir (0.1-1-10-25-50 µM), used alone or in combination, evaluating the impact of these drugs in terms of mitochondrial activity, with MTT cell proliferation assay; mRNA expression of heme oxygenase (HemeOH) and reactive oxygen species (ROS) levels with 2',7'-dichlorofluorescin diacetate (H2DCFDA) in order to assess oxidative stress; apoptotic cell death with flow cytometry. Results: We observed that Lopinavir and Ritonavir treatment, at 25 and/or 50 µM concentrations, induced mitochondrial damage, increase of heme oxygenase RNA expression levels and ROS generation, followed by apoptosis in SH-SY5Y. Conclusions: Our in vitro model demonstrates a damaging effect of HIV protease inhibitors on the neuroblastoma cell line, thus partially mimicking the impact of these drugs on the CNS of children born to HIV positive mothers undergone to antiretroviral treatment.

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Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

Cited by 59 publications

References 179 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

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication

HIV Protease Inhibitors Apoptotic Effect in SH-SY5Y Neuronal Cell Line

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