Controversies in HIV-associated neurocognitive disorders

Nightingale, Sam; Winston, Alan; Letendre, Scott; Michael, Benedict; McArthur, Justin C.; Khoo, Saye; Solomon, Tom

doi:10.1016/s1474-4422(14)70137-1

Cited by 251 publications

(200 citation statements)

References 96 publications

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“…In light of the above considerations and the fact that neurocognitive impairment affects more than 50% of HIV-1-infected individuals (Nightingale et al, 2014), we performed a pilot study in cART-treated HIV-1-positive patients with long-term virologic suppression. The aims…”

Section: Introductionmentioning

confidence: 99%

A pilot study on the effects of probiotic supplementation on neuropsychological performance and microRNA‐29a‐c levels in antiretroviral‐treated HIV‐1‐infected patients

et al. 2017

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Section: Introductionmentioning

confidence: 99%

A pilot study on the effects of probiotic supplementation on neuropsychological performance and microRNA‐29a‐c levels in antiretroviral‐treated HIV‐1‐infected patients

et al. 2017

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“…Because brain HO-1 deficiency is associated with cognitive impairment in HIV-infected individuals, we have proposed making HO-1 a therapeutic target for neuroprotection against HIV as an adjunctive therapy to antiretroviral therapy (ART) for preventing the pathogenic effects of HIV infection of the CNS (1,3). HIV infection is associated with a syndrome of cognitive dysfunction (HIV-associated neurocognitive disorders [HAND]) in up to 50% of ART-treated HIV-infected individuals (12)(13)(14), which is thought to result in part from persistent inflammation and oxidative stress within both the CNS and systemic compartments (15). Within the CNS, such effects are driven largely by HIV infection of macrophages and microglia, long-lived HIV reservoirs that persist in ART-treated individuals (16).…”

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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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“…In relation to cognitive impairment in HIV, potential influencing factors may be incomplete viral suppression in the central nervous system (CNS) of HIV-infected patients, increased age, poor CNS penetration of some antiretroviral drugs, time of antiretroviral exposure, presence of drug resistance and psychiatric comorbidities (Ciccarelli et al, 2013;Nightingale et al, 2014;Rosca, Rosca, Chirileanu, & Simu, 2011;Woods et al, 2009). It is also noteworthy that persistent cognitive impairment in HIV-infected stable patients is generally attributed to inflammatory influences.…”

Section: Discussionmentioning

confidence: 99%

Cognitive impairment in HIV and HCV co-infected patients: a systematic review and meta-analysis

et al. 2016

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Cognitive impairment has been well documented in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) mono-infections. However, in the context of HIV/HCV co-infection the research is more limited. The aim of this systematic review was to describe the characteristics of cognitive impairment in HIV/HCV co-infection and to examine the differences in cognitive performance between HIV/HCV and HIV and HCV mono-infected patients. Of the 437 records initially screened, 24 papers met the inclusion criteria and were included in the systematic review. Four studies were included in the meta-analysis. Most studies indicated that HIV/HCV co-infected patients had a higher level of cognitive impairment than HIV mono-infected patients. Meta-analysis also indicated that HIV mono-infected patients had a significantly lower global deficit score than co-infected patients. The results also indicated that co-infected patients were more likely to be impaired in information processing speed than HIV mono-infected patients. These findings can be challenged by biasing factors such as the small number of included studies, heterogeneity of the samples and a large diversity of methodological procedures. Future research with consistent and comprehensive neuropsychological batteries and covering a greater diversity of risk factors is needed, in order to clarify the effects of both viruses on cognitive function and the mechanisms that underlie these effects. Because cognitive impairments may pose significant challenges to medication adherence, quality of life and overall functioning, such knowledge may have important implications to the planning and implementation of effective interventions aimed at optimising the clinical management of these infections. ARTICLE HISTORY

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Controversies in HIV-associated neurocognitive disorders

Cited by 251 publications

References 96 publications

A pilot study on the effects of probiotic supplementation on neuropsychological performance and microRNA‐29a‐c levels in antiretroviral‐treated HIV‐1‐infected patients

A pilot study on the effects of probiotic supplementation on neuropsychological performance and microRNA‐29a‐c levels in antiretroviral‐treated HIV‐1‐infected patients

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

Cognitive impairment in HIV and HCV co-infected patients: a systematic review and meta-analysis

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