The impact of HIV-1 on neurogenesis: implications for HAND

Ferrell, Darren; Giunta, Brian

doi:10.1007/s00018-014-1702-4

Cited by 37 publications

(28 citation statements)

References 51 publications

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“…ART-related factors Late commencement of ART 117 ART side effects (metabolic, neurotoxicity) 118 Low CPE scores 94 Low ME scores 119 Sub-optimal ART adherence 110 ART resistance 110 Co-morbidities CVD (hypertension, diabetes, obesity, hypercholesteremia, stroke) [116][117][118] Viral co-infection (HCV, HTLV, HIV- Abbreviations: ART, antiretroviral therapy; CPE, central penetrating effectiveness; ME, monocyte efficacy; CVD, cardiovascular disease; HCV, Hepatitis C virus; HTLV, Human T-lymphotropic virus; CMV, cytomegalovirus; PTSD, post-traumatic stress disorder.…”

Section: Duration Of Infection 115mentioning

confidence: 99%

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

Michael

Mpofana

Ramlall

et al. 2020

NDT

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Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remains prevalent in the anti-retroviral (ART) era. While there is a complex interplay of many factors in the neuropathogenesis of HAND, decreased neurotrophic synthesis has been shown to contribute to synaptic degeneration which is a hallmark of HAND neuropathology. Brain derived neurotrophic factor (BDNF) is the most abundant and synaptic-promoting neurotrophic factor in the brain and plays a critical role in both learning and memory. Reduced BDNF levels can worsen neurocognitive impairment in HIV-positive individuals across several domains. In this paper, we review the evidence from pre-clinical and clinical studies showing the neuroprotective roles of BDNF against viral proteins, effect on co-morbid mental health disorders, altered human microbiome and ART in HAND management. Potential applications of BDNF modulation in pharmacotherapeutic, cognitive and behavioral interventions in HAND are also discussed. Finally, research gaps and future research direction are identified with the aim of helping researchers to direct efforts to make these BDNF driven interventions improve the quality of life of patients living with HAND.

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Section: Duration Of Infection 115mentioning

confidence: 99%

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

Michael

Mpofana

Ramlall

et al. 2020

NDT

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“…Since the start of the antiretroviral treatment (ART) era, HIV-1-associated co-morbidities have manifested in the clinical population, most notably HIV-associated neurocognitive disorders (HAND), accelerated aging, cardiovascular diseases, and metabolic dysfunction [ 1 ]. HAND continues to affect over 50% of all HIV-1-infected patients, even while undergoing ART treatment [ 2 , 3 ]. This disorder describes a specific spectrum of neurocognitive impairments such as asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD) [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Adult neurogenic deficits in HIV-1 Tg26 transgenic mice

Putatunda

Zhang

et al. 2018

J Neuroinflammation

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BackgroundEven in the antiretroviral treatment (ART) era, HIV-1-infected patients suffer from milder forms of HIV-1-associated neurocognitive disorders (HAND). While the viral proteins Tat and gp120 have been shown to individually inhibit the proliferation and neural differentiation of neural stem cells (NSCs), no studies have characterized the effects of all the combined viral proteins on adult neurogenesis.MethodsThe HIV-1 Tg26 transgenic mouse model was used due to its clinical relevance to ART-controlled HIV-1-infected patients who lack active viral replication but suffer from continuous stress from the viral proteins. Quantitative RT-PCR analysis was performed to validate the expression of viral genes in the neurogenic zones. In vitro stemness and lineage differentiation assays were performed in cultured NSCs from HIV-1 Tg26 transgenic mice and their wild-type littermates. Hippocampal neurogenic lineage analysis was performed to determine potential changes in initial and late differentiation of NSCs in the subgranular zone (SGZ). Finally, fluorescent retroviral labeling of mature dentate granule neurons was performed to assess dendritic complexity and dendritic spine densities.ResultsVarying copy numbers of partial gag (p17), tat (unspliced and spliced variants), env (gp120), vpu, and nef transcripts were detected in the neurogenic zones of Tg26 mice. Significantly fewer primary neurospheres and a higher percentage of larger sized primary neurospheres were generated from Tg26 NSCs than from littermated wild-type mouse NSCs, implying that Tg26 mouse NSCs exhibit deficits in initial differentiation. In vitro differentiation assays revealed that Tg26 mouse NSCs have reduced neuronal differentiation and increased astrocytic differentiation. In the SGZs of Tg26 mice, significantly higher amounts of quiescent NSCs, as well as significantly lower levels of active NSCs, proliferating neural progenitor cells, and neuroblasts, were observed. Finally, newborn mature granule neurons in the dentate gyri of Tg26 mice had deficiencies in dendritic arborization, dendritic length, and dendritic spine density.ConclusionsBoth in vitro and in vivo studies demonstrate that HIV-1 Tg26 mice have early- and late-stage neurogenesis deficits, which could possibly contribute to the progression of HAND. Future therapies should be targeting this process to ameliorate, if not eliminate HAND-like symptoms in HIV-1-infected patients.

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“…Past reports have indicated a link between HIV-1 and reduced proliferation of neural stem cells (NSCs) as well as reduced neurogenesis 3 . Although HIV does not infect mature neurons, the virus has been shown to infect NSCs 4 .…”

Section: Introductionmentioning

confidence: 99%

HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

et al. 2016

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The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite combination antiretroviral therapy (cART). There is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6J mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV.

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The impact of HIV-1 on neurogenesis: implications for HAND

Cited by 37 publications

References 51 publications

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

Adult neurogenic deficits in HIV-1 Tg26 transgenic mice

HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

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