Correction to: Aging and apolipoprotein E in HIV infection

The row describing the clinical study of Mukerji et al. (2016) was inadvertently deleted during the compilation of Table 3. As a result, the citation for Mukerji et al. (2016) was not included in the "References" section of the manuscript

Aging and Apolipoprotein E in HIV Infection

With the implementation of increasingly effective antiretroviral therapy (ART) over the past three decades, individuals infected with HIV live a much longer life. HIV infection is no longer a terminal but rather a chronic disease. However, the lifespan of infected individuals remains shorter than that of their uninfected peers. Even with ART, HIV infection may potentiate “premature” aging. Organ-associated disease and systemic syndromes that occur in treated HIV-infection are like that of older, uninfected individuals. Brain aging may manifest as structural changes or neurocognitive impairment that are beyond the chronological age. The spectrum of neurological, cognitive, and motor deficiencies, currently described as HIV-associated neurocognitive disorders (HAND), may reflect earlier onset of mechanisms common to HIV infection and aging (accelerated aging). HAND could also reflect the neurological impact of HIV infection superimposed on comorbidities linked to age and chronic inflammation, leading to a higher prevalence of neurocognitive impairment across the age span (accentuated aging). In addition, apolipoprotein E (ApoE), one of the most influential host risk factors for developing Alzheimer’s disease, has been implicated in the development of HAND. But studies differ as to whether ApoE is relevant, and whether age and ApoE interact to impair brain function in the HIV-infected patient. What is clear is that HIV-infected individuals are living longer with HIV, and therefore factors related to aging and health need to be examined in the context of current, effective ART. This review addresses the recent evidence for the influence of aging and ApoE on HIV-associated neurocognitive impairment

Maturing neurons are selectively sensitive to human immunodeficiency virus type 1 exposure in differentiating human neuroepithelial progenitor cell cultures

Human immunodeficiency virus type 1 (HIV-1) infection of the brain is associated with neuronal injury manifested by dendritic pruning, aberrant neurofilament metabolism, and decreased synaptic density. The central nervous system (CNS) responds to neuronal injury by differentiating new neurons and astrocytes from resident populations of multipotent neuroepithelial progenitor cells (NEP) located in regions such as the subventricular zone or hippocampus. In vitro studies have demonstrated that the HIV-1 virion or envelope glycoprotein gp120 can injure differentiated human neurons and astrocytes, suggesting that HIV-1 proteins could similarly injure NEP or NEP-derived glial and neuronal lineage-committed precursor cells. To answer this question, human fetal brain-derived “neurospheres” containing NEP and NEP-derived precursor cells were cultured in low serum differentiation medium containing lymphotropic HIV-1(SF2), macrophage-tropic HIV-1(SF128A), or recombinant gp120SF2 from HIV-1(SF2). These experiments indicate that exposure to HIV-1 does not affect the ability of the NEP to differentiate into cells expressing either astrocyte-specific or neuron-specific cytoskeletal antigens. However prolonged exposure to HIV-1 does selectively decrease expression of neuronal antigens (microtubule β-III-tubulin and intermediate filament neurofilament-L) but not astrocyte antigens (intermediate filament glial fibrillary acidic protein). The effects of continuous exposure to HIV-1 or gp120 may result from injury to developing neurons and/or impairment of the neuronal developmental process itself. By depressing neuronal microtubule and neurofilament protein expression, HIV-1 and gp120 exposure compromise the potential for postmitotic neuronal dendrite and axon development

Depressed neurofilament expression associates with apolipoprotein E3/E4 genotype in maturing human fetal neurons exposed to HIV-1

Exposure of differentiating human neural progenitor cells (NEP) to HIV-1 results in a neuronal“failure to thrive” phenotype characterized by a relative decrease in neurofilament-light (NF-L) expression. However,when NEP were segregated by their apolipoproteinE genotype, differentiating apolipoprotein E3/E4 cells showed reduced NF-L expression upon HIV-1 exposure,but differentiating apolipoprotein E3/E3 or apolipoproteinE4/E4 cells did not. These data suggest that apolipoproteinE genotype is a host factor that could affect the development of neurocognitive dysfunction in HIV-1 infected individuals

A two-culture method for exposure of human brain organotypic slice cultures to replicating human immunodeficiency virus type 1

To evaluate the effect of HIV-1 virus on neural cells, we have developed a method to culture human fetal organotypic brain slices in the presence of live virus. Brain slices were placed on semipermeable hydrophilic membrane inserts, resting on top of wells that contain cultured H9 T-cells chronically producing HIV-1. This system allows free exposure of the brain slices to HIV-1, HIV-1 proteins, and other molecules released by the infected T-cells. After specific lengths of time in culture, slices were stained for viability with Calcein-AM and propidium iodide, for neural cell markers such as GFAP, nestin and β-III-tubulin, tested for cell proliferation, and analyzed by fluorescent and confocal microscopy. When cultured in the presence of neural progenitor medium lacking serum, slices were viable and maintained active cell replication for at least 3 weeks in culture, without significant cell death. By comparison with slices co-cultured with uninfected T-cells or with medium alone, slices cultured in the presence of HIV-1 showed increased nestin and GFAP. Moreover, in slices exposed to HIV-1-producing H9 cells, regions of nestin stain were, over time in culture, replaced with GFAP stain. This suggested the process of gliosis often found in brains of HIV-1 infected individuals. This co-culture method can be used to model the dynamics and the microenvironment of brain tissue exposed to HIV-1 and can potentially be used to test therapies directed at preventing HIV-1-induced neural damage

A longitudinal assessment of autologous neutralizing antibodies in children perinatally infected with human immunodeficiency virus type 1

The evolution of autologous neutralizing antibodies to sequential human immunodeficiency virus type 1 (HIV-1) isolates was studied in a population of 16 children who were perinatally infected with human immunodeficiency virus type 1. The cohort included seven children with rapid disease progression (RP) and nine who had nonrapid disease progression (NRP). Four of the NRP after 6 months of age harbored viruses that could be neutralized by antibodies found in autologous contemporaneous plasma (titers up to 1:640) while the majority of longitudinally collected viruses from five NRP were resistant to neutralization with contemporaneous plasma. Because of their shorter survival, only five of the RP had studies after 6 months of age; three of the five had neutralizing antibodies to contemporaneous virus isolates and the highest titers were 1:20. The highest titers in RP (up to 1:160) occurred in specimens obtained prior to 6 months of age but these were most likely of maternal origin. Most isolates that were not neutralized by contemporaneous plasma could be neutralized using noncontemporaneous plasma obtained months to years after the virus isolates. These autologous noncontemporaneous neutralizing antibodies persisted for years, had titers that were higher to viruses isolated at younger ages, and were generally more potent in children with NRP than RP. Demonstration of neutralizing antibodies to viruses previously resistant to neutralization by contemporaneous plasma suggests a continuous evolution of virus variants in vivo that are able to escape the effect of neutralizing antibodies

Apolipoprotein E-Dependent Differences in Innate Immune Responses of Maturing Human Neuroepithelial Progenitor Cells Exposed to HIV-1

HIV enters the brain early during infection and induces a chronic inflammatory state that can result in neurological abnormalities in a subset of infected individuals. To investigate the effects of HIV exposure on neurogenesis and neuronal survival in the brain, we have used a model system consisting of human neuroepithelial progenitor (NEP) cells that undergo directed differentiation into astrocytes and neurons in vitro. Changes in gene expression in NEP cultures as a result of HIV exposure were investigated using gene expression microarrays with the Illumina HT-12 V4_0_R1 platform array. Through this approach, we identified a group of genes specifically upregulated by exposure to virus that are strongly related to interferon induced responses and antigen presentation. When the data were stratified by their apolipoprotein genotype, this innate immune response was more robust in the apolipoprotein E3/E3 genotype cultures than in the apolipoprotein E3/E4 counterparts. Biological processes as defined by the gene ontology (GO) program were also differently affected upon virus exposure in cultures of the two genotypes, particularly those related to antigen presentation and the actions of interferons. Differences occurred in both in numbers of genes affected and their significance in the GO processes in which they participate, with apoE3/E3 > apoE3/E4. These data suggest that maturing NEP cultures recognize HIV and respond to it by mounting an innate immune response with a vigor that is influenced by the apolipoprotein E genotype of the cells

Cellular Tropisms and Co-receptor Usage of HIV-1 Isolates from Vertically Infected Children With Neurological Abnormalities and Rapid Disease Progression

The longitudinal evolution of HIV-1 phenotypes was studied in a cohort of six vertically infected children with early onset and rapid progression of clinical disease. Among 30 viral isolates obtained from peripheral blood, tropisms for both human blood-derived cells (macrophages, T-lymphocytes), and for human neural (brain-derived) cells (microglia, astrocytes) were determined, as was chemokine co-receptor usage. All children harbored from birth macrophage-tropic isolates using the CCR5 co-receptor. Two children later developed T-cell tropic isolates with CXCR4 and CCR3 usage. While all six patients developed neurological abnormalities, only three produced neural cell tropic isolates, which used CCR5. However, early and persistent finding of both astrocyte- and microglia-tropic isolates in one patient did associate with the most rapid progression to brain atrophy among the six patients. Viral phenotypic properties determined in cell culture did not specifically predict clinical features or course, and the development of AIDS did not coincide with, or depend on, the appearance T-tropic, syncytia-inducing viruses

Fingolimod induces neuronal-specific gene expression with potential neuroprotective outcomes in maturing neuronal progenitor cells exposed to HIV

Fingolimod (FTY720), a structural analogue of sphingosine, targets sphingosine-1-phosphate receptor signaling and is currently an immunomodulatory therapy for multiple sclerosis. Fingolimod accesses the central nervous system (CNS) where its active metabolite, fingolimod phosphate (FTY720-P), has pleotropic neuroprotective effects in an inflammatory microenvironment. To investigate potential neuronal-specific mechanisms of fingolimod neuroprotection, we cultured the human neuronal progenitor cell line, hNP1, in differentiation medium supplemented with HIV- or Mock-infected supernatants, with or without FTY720-P. Gene expression was investigated using microarray and functional genomics. FTY720-P treatment increased differentially expressed (DE) neuronal genes by 33% in HIV-exposed and 40% in Mock-exposed cultures. FTY720-P treatment broadened the functional profile of DE genes in HIV-exposed versus Mock-exposed neurons, including not only immune responses but also transcriptional regulation and cell differentiation, among others. FTY720-P treatment downregulated the gene for follistatin, the antagonist of activin signaling, in all culture conditions. FTY720-P treatment differentially affected both glycolysis-related and immune response genes in Mock- or HIV-exposed cultures, significantly upregulating 11 glycolysis-related genes in HIV-exposed neurons. FTY720-P treatment also differentially upregulated genes related to innate immune responses and antigen presentation in Mock-exposed and more so in HIV-exposed neurons. However, in HIV-exposed neurons, FTY720-P depressed the magnitude of differential expression in almost half the genes, suggesting an anti-inflammatory potential. Moreover, in HIV-exposed neurons, FTY720-P reduced expression of the amyloid precursor protein (APP) gene, resulting in reduced expression of the APP protein. This study provides new evidence that fingolimod alters neuronal gene expression in inflammatory, viral-infected microenvironments, with the potential for neuroprotective effects