Biomedical subjects

Eugene O Major

Publications and source records attributed to Eugene O Major.

At least 19 recordsLinked to original sources

PubMed2007

Induction of original phenotype of human immortalized chondrocytes: a quantitative gene expression analysis.

We previously established a line of immortalized normal human articular chondrocytes, lbpva55, expressing the E6 and E7 transforming genes of the human papilloma virus type 16. With this study we investigated the phenotypic modulation ability of this cell line, cultured in different conditions, with the aim of validating its use for studies on cartilage metabolism and physiology. To this end, we performed a quantitative analysis, using real-time PCR technology, of the expression of the main structural components of the cartilage matrix (collagens I, II and aggrecan), of two transcription factors regulating chondrocyte differentiation (Sox-9 and Egr-1) and of some enzymes involved in matrix turnover (cathepsin B, MMP-1 and MMP-13). Results showed that, under defined conditions, lbpva55 cells were able to re-express the chondrocyte phenotype that was lost in a conventional monolayer condition, as demonstrated by an up-regulation of collagen II, the main marker of hyaline cartilage and Sox-9, a master gene regulator of chondrocytic differentiation. The gene expression profile of our immortalized cells compared with that of normal articular chondrocytes showed that this line could be used as a valid in vitro model for a better understanding of cell molecular mechanisms relevant for the development of new therapeutic approaches in rheumatic diseases and for the cartilage engineering field.

Cell Line↗

PubMed2006

Interactions between c-Jun, nuclear factor 1, and JC virus promoter sequences: implications for viral tropism.

The infectious cycle of the human polyomavirus JC (JCV) is ultimately regulated in cellular nuclei at the level of viral protein expression and genomic replication. Such activity is prompted by interactions between variant nucleotide sequences within the JCV regulatory region (promoter) and cellular transcription factors that bind specific DNA consensus sites. In previous work we identified an NF-1 class member, NF-1X, as a critical transcription factor affecting the JCV cellular host range. Within variant JCV promoters, as well as other viral and cellular promoters, adjacently located NF-1 and AP-1 consensus sites are often found. The close proximity of these two binding sites suggests the opportunity for interaction between NF-1 and AP-1 proteins. Here, by electrophoretic mobility shift assays, we show temporal and dose-dependent interference by an AP-1 family member, c-Jun, upon NF-1 proteins binding an NF-1 consensus site derived from JCV promoter sequence. Moreover, as demonstrated by protein-protein interaction assays, we identify specific binding affinity independent of DNA binding between NF-1X and c-Jun. Finally, to compare the binding profiles of NF-1X and c-Jun on JCV promoter sequence in parallel with in vivo detection of viral activity levels, we developed an anchored transcriptional promoter (ATP) assay. With use of extracts from JCV-infected cells transfected to overexpress either NF-1X or c-Jun, ATP assays showed concurrent increases in NF-1X binding and viral protein expression. Conversely, increased c-Jun binding accompanied decreases in both NF-1X binding and viral protein expression. Therefore, inhibition of NF-1X binding by c-Jun appears to play a role in regulating levels of JCV activity.

Binding Sites↗

PubMed2006

Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients. METHODS: We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI. RESULTS: Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000). CONCLUSIONS: A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.

Antibodies, Monoclonal↗

PubMed2006

Astrocyte differentiation selectively upregulates CCL2/monocyte chemoattractant protein-1 in cultured human brain-derived progenitor cells.

Chemokines (chemoattractant cytokines) and their receptors are present in the brain and may play roles in both neurodevelopment and neuropathology. Increased brain levels of monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, are found in patients with human immunodeficiency virus type 1 (HIV-1)-associated dementia and other acute and chronic neurologic diseases. Although the function of CCL2 in the brain is unclear, it is believed that upregulation of this chemokine during neuropathologic or neuroinflammatory conditions leads to recruitment of activated monocytes into the brain, where they differentiate into macrophages producing neurotoxic and inflammatory molecules. We recently showed that human fetal brain-derived progenitor cells are susceptible to HIV-1 and JC virus infection, and that differentiation toward an astrocyte phenotype increased virus production from these cells. In the current study, we found that in the absence of infection, progenitors produced moderate levels of CCL2 (5.6 ng per million cells). Astrocyte differentiation over 3 weeks increased CCL2 protein levels 30-fold in a biphasic manner, whereas neuronal differentiation decreased production 20-fold. Electromobility shift assays (EMSAs) demonstrated increased nuclear NF-kappaB levels within 2 h of initiating astrocyte differentiation, and inhibitors of NF-kappaB activation partially blocked the CCL2 increase in differentiating astrocytes. Transfection of progenitors with mutated CCL2 promoter/CAT reporter constructs showed that the distal promoter region, containing NF-kappaB and NF-I binding sites, is important for differentiation-induced CCL2 upregulation. Together these results suggest that the transcription factor NF-kappaB, and possibly NF-I, contribute to the upregulation of CCL2 chemokine production during the differentiation of human progenitor cells toward an astrocyte phenotype.

AIDS Dementia Complex↗

PubMed2006

Complete replication cycle and acquisition of tegument in nucleus of human herpesvirus 6A in astrocytes and in T-cells.

The ultrastructural replication cycle of human herpesvirus 6A and 6B, both T-lymphotropic viruses, with tropism for the central nervous system, was compared by electron microscopy in the same cells, that is, in the T-lymphoblastoid cell line SupT-1 and in human astrocytes. Both HHV-6A and HHV-6B replicated efficiently in SupT-1 and formed viral particles. The tegument is the least characterized structure of the herpesviral particle and both variants were able to form intranuclear membrane compartments called tegusomes in SupT-1 where tegumentation occurred. Also, tegumentation occurred in HHV-6A infected cells in the nucleoplasm without the presence of a tegusome. This suggests that there is more than one possible route of tegumentation. Differences in the replication cycles between HHV-6A and HHV-6B were also observed in the cytoplasm. One such difference was that prominent annulate lamellae were only found in the cytoplasm of HHV-6A infected cells. In astrocytes a successful formation of viral particles was only seen with the HHV-6A variant. The HHV-6A virus life cycle in astrocytes resembled the life cycle in the T-cell line SupT-1, except that no annulate lamellae were found. Complete viral particles were found extracellularly around the astrocytes and the supernatant of infected astrocytes were able to re-infect SupT-1 cells. This suggests that HHV-6A infection in astrocytes can generate complete, viable, and infectious viral particles. The HHV-6 variants behave differently in the same type of cells and have different tropisms for astrocytes, supporting the notion that the variants might induce different diseases.

Astrocytes↗

PubMed2006

Viral proteomics: a promising approach for understanding JC virus tropism.

The human polyomavirus JC virus (JCV) is responsible for the CNS demyelination observed in cases of progressive multifocal leukoencephalopathy. The JCV regulatory region (promoter) is a hypervariable, noncoding, nucleotide sequence positioned between the early and late protein-coding regions in the viral genome. Selective binding of cellular transcription factors to this promoter region participates in the control of viral tropism. Hence, further study of these proteins might provide new insights into JCV tropism and associated pathogenesis. This review gives an overview of viral proteomics - the study of all proteins expressed from the viral gene transcripts, and all the cellular proteins that play a role in JCV tropism. It also describes a new biochemical approach for studying relevant JCV promoter-binding proteins, which is an anchored-JCV transcriptional promoter (ATP) assay. An ATP assay utilizes the product of PCR-amplified JCV promoter sequences coupled with Sepharose beads in order to capture and isolate cellular nuclear proteins with specific promoter-binding affinity for analysis. Proteins that bind to JCV-ATPs can be eluted and subjected to proteomic analysis. Insights from this approach may improve the understanding of viral and cellular parameters that control JCV tropism.

Deoxyribonuclease I↗

PubMed2006

JC virus can infect human immune and nervous system progenitor cells: implications for pathogenesis.

Recent advances in stem cell biology have called attention to the role these cells may play in the pathogenesis of systemic and nervous system diseases. Although not capable of indefinite self renewal and pluripotentiality as stem cells are, progenitor cells can give rise to cells of different lineages. It is infection of these differentiated cells that has traditionally been associated with the pathology and symptoms of viral-induced disease. However, neural progenitor cells have been shown, in vitro, to be susceptible to infection by neurotropic viruses such as the human polyomavirus, JCV, and the lentivirus, HIV-1. These progenitor cells, which exist during development as well as in the fully developed adult brain, could therefore be involved in neuropathogenesis. Morever, JCV can also infect progenitor cells of the hematopoietic system, derivatives of which have been implicated in the trafficking of virus from the periphery to the brain. Interestingly, susceptibility to and molecular regulation of JCV infection in hematopoietic cells closely parallels what has been observed in glial cells. The biological interaction between the immune and nervous systems that exists in the dissemination of virus from periphery to nervous system and the susceptibility of both systems to JCV infection provide potential for hematopoietic and neural progenitor cell involvement in JCV pathogenesis.

B-Lymphocytes↗

PubMed2006

Neural progenitors and HIV-1-associated central nervous system disease in adults and children.

The human immunodeficiency virus type 1 (HIV-1) is a neurotrophic lentivirus that enters and infects the central nervous system (CNS) of adults and children, giving rise to the clinical syndromes of AIDS-dementia complex (ADC) in adults and HIV-1-associated progressive encephalopathy (PE) in pediatric patients. The clinical presentation and progression of neuroAIDS in the developing brain of children is distinct from that seen in adult patients. Neuroimaging, and upon autopsy, neuropathological findings corresponding to clinical disease in pediatric patients include impaired brain growth, reactive gliosis, myelin pallor, calcifications of the basal ganglia, cortical and cerebral atrophy with neuronal loss and ventricular enlargement, and abnormalities of cerebral vasculature. Although there is some overlap with neuropathologic findings in adult patients, ADC in adults is more typically a late development, often complicated by opportunistic infections of the CNS. The neuropathogenesis of ADC and PE is incompletely understood. One population of CNS cells critical for brain development and response to injury and inflammation are neural progenitors cells, and it has therefore been suggested that these cells may be involved in the neuropathogenesis of ADC, and especially PE. This review examines the neurobiology of neural progenitor cells and the possibility that HIV-1 infection of neural progenitors, exposure of neural progenitors to virus, viral products, or progenitor exposure to HIV-1 associated neuroinflammatory substances and neurotoxins might contribute to the neuropathogenesis of AIDS in adults and children. That some of the clinical differences between ADC and PE might, in part, be explained by differences in neural progenitor involvement will also be considered.

AIDS Dementia Complex↗

PubMed2005

Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories.

JC virus (JCV), BK virus (BKV) and simian virus 40 (SV40) may be associated with human brain tumors. These polyomaviruses have been shown to induce brain tumors in experimentally infected animals. Several studies have found polyomavirus genomic sequences in human brain tumor tissues by using polymerase chain reaction (PCR), while others have not. Inconsistencies in previous findings may be due in part to small sample sizes and differences in underlying patient populations, laboratory techniques and quality control measures. To assess the role of polyomaviruses in human brain tumors and address inconsistencies of previous reports, we investigated the prevalence of viral sequences in a series of 225 brain tumor tissue specimens in 2 independent laboratories. PCR followed by Southern hybridization was performed at the National Institute of Neurological Disorders and Stroke (NINDS). Real-time quantitative PCR was performed on the same tissues at Johns Hopkins University (JHU). Only those tumors with amplifiable DNA were tested further for polyomavirus sequences. Positive and negative control tissues were included, and all specimens were masked. Amplifiable DNA was detected in 225/225 (100%) tumors at NINDS, 9 (4%) of which contained polyomavirus sequences (3 JCV-positive, 3 BKV-positive and 3 SV40-positive). The JHU laboratory amplified DNA from 165/225 (73%) tumors, of which 1 tumor tested positive (for SV40). No tumors tested positive in both laboratories. Results for masked quality control tissues were concordant between laboratories. Nucleotide sequences for JCV, BKV and SV40 are rarely present in a large series of adult and pediatric brain tumors.

Adolescent↗

PubMed2005

Donor origin of BK virus in renal transplantation and role of HLA C7 in susceptibility to sustained BK viremia.

In a previous study, we performed serial BK virus (BKV), polymerase chain reaction (PCR) and detected active BKV infection in 70 (35.4%) of 198 renal transplant recipients. In the current study, pre-transplant donor and recipient samples were analyzed for BKV antibody titer and HLA alleles. Donor antibody titer was inversely proportional to onset of viruria, p<0.001, directly proportional to duration of viruria, p=0.014 and directly proportional to peak urine viral titer p=0.005. Recipient pairs receiving kidneys from the same donor were concordant for BKV infection, p=0.017, and had matched sequences of segments of the NCCR and VP1 genes that tended to vary among recipients of kidneys from different donors. We did not see an association of HLA A, B, or DR, HLA allele mismatches or total HLA mismatches and BK infection. However, all 11 recipients with sustained BK viremia received kidneys from donors lacking HLA C7, and 10 recipients also lacked C7. These findings derive from the largest and most comprehensive prospective study of BKV infection in renal transplant recipients performed to date. Our data support donor origin for early BKV infection in kidney transplant recipients, and suggest that a specific HLA C locus may be associated with failure to control BKV infection.

Alleles↗

PubMed2005

Herpes simplex virus type 1 enters human epidermal keratinocytes, but not neurons, via a pH-dependent endocytic pathway.

Herpes simplex virus (HSV) enters some laboratory cell lines via a pH-dependent, endocytic mechanism. We investigated whether this entry pathway is used in human cell types relevant to pathogenesis. Three different classes of lysosomotropic agents, which raise endosomal pH, blocked HSV entry into primary and transformed human keratinocytes, but not into human neurons or neuroblastoma lines. In keratinocytes, incoming HSV particles colocalized with markers of endocytic uptake. Treatment with the isoflavone genistein, an inhibitor of protein tyrosine kinases, reduced the delivery of incoming viral particles to the nuclear periphery and virus-induced gene expression in keratinocytes but not neurons. Moreover, in keratinocyte monolayer islets, HSV infected both the inner and outer cells in a genistein-sensitive manner, suggesting viral endocytosis from both basolateral and apical plasma membrane surfaces. Together, the results indicate that HSV enters human epidermal keratinocytes, but not neurons, by a low-pH, endocytic pathway that is dependent on host tyrosine phosphorylation. Thus, HSV utilizes fundamentally different cellular entry pathways to infect important target cell populations.

Animals↗

PubMed2005

Variant-specific tropism of human herpesvirus 6 in human astrocytes.

Though first described as a lymphotropic virus, human herpesvirus 6 (HHV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra- and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra- and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HHV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes.

Astrocytes↗

PubMed2004

Differential effects of interferon-gamma on the expression of cyclooxygenase-2 in high-grade human gliomas versus primary astrocytes.

We compared effects of interferon-gamma (IFNgamma) on cyclooxygenase-2 (COX-2) expression in malignant human glioma cell lines and cultured primary human astrocytes. While IFNgamma inhibited interleukin-1beta (IL1beta)-induced expression of COX-2 in the glioma cells, it enhanced expression in primary astrocytes. This differential effect correlated with the observed modulation of NFkappaB and AP-1 DNA binding activity; reduced in the glioma cells, increased in primary astrocytes. Furthermore, IFNgamma had a significantly greater anti-proliferative effect on the glioma cells than COX inhibitors. This inhibitory effect of IFNgamma on expression of COX-2 in human glioma cells may have relevance for immunotherapies directed against high-grade gliomas.

Astrocytes↗

PubMed2004

Nuclear receptor activation and interaction with morphine.

Nervous system disease in HIV infection is associated with toxic damage induced by effects from proinflammatory responses and oxidative stress, and such effects may be more prominent among opioid abusers. In these studies, the effects of activating retinoid receptor (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) and peroxisome proliferator activated receptor (PPAR) gamma, which belong to the steroid-lipid nuclear receptor family, on tumor necrosis factor (TNF)-alpha production and inducible nitric oxide synthase (iNOS) gene expression by stimulated U937 and SVG cells, respectively, were examined. Also studied were the effects of morphine on these responses. These studies showed that, in stimulated cells, the observed responses were suppressed by activation of the nuclear receptors as compared to non-stimulated control cells. Moreover, in phytohemagglutinin (PHA)-stimulated U937 cells, morphine reversed the TNF-alpha suppression that was induced by LG101305 and ciglitazone. Preliminary data in SVG cells suggest a tendency for morphine to have a similar effect on LG101305-exposed SVG cells stimulated with a combination of lipopolysaccharide (LPS) and interferon-gamma, whereas this effect was not induced when these cells were incubated with ciglitazone. Therefore, specific nuclear receptor activation may be potentially beneficial in the treatment of neurological disease associated with HIV infection and may show specific interactions with opioids. The mechanisms that underlie these effects require further study.

Astrocytes↗

PubMed2004

Comparison of PCR-southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid.

The presence of the human polyomaviruses JCV and BKV in immunocompromised patients can lead to lethal diseases and conditions including progressive multifocal leukoencephalopathy (PML), interstitial nephritis, hemorrhagic cystitis, and kidney allograft rejection. Typically, detection of JCV and BKV in clinical samples has employed standard PCR amplification for viral nucleotide sequences, with subsequent confirmation for viral genome specificity of PCR products by southern blot hybridization. Here, we directly tested a validated PCR-southern protocol with a TaqMan real-time PCR protocol (Applied Biosystems) to assay clinical samples of urine and cerebrospinal fluid. We found equal specificity and sensitivity with both methods. However, real-time allowed for absolute viral-genome quantitation without the use of radionucleotides and was performed more rapidly, in as little as 24 h. Such advantages are important to consider in the effort to establish international standardization of controls for the detection of JCV and BKV, which would aid in screening confidence and the reliable assessment of anti-viral therapies.

BK Virus↗

PubMed2004

Human immunodeficiency virus type 1 infection of human brain-derived progenitor cells.

Although cells of monocytic lineage are the primary source of human immunodeficiency virus type 1 (HIV-1) in the brain, other cell types in the central nervous system, including astrocytes, can harbor a latent or persistent HIV-1 infection. In the present study, we examined whether immature, multipotential human brain-derived progenitor cells (nestin positive) are also permissive for infection. When exposed to IIIB and NL4-3 strains of HIV-1, progenitor cells and progenitor-derived astrocytes became infected, with peak p24 levels of 100 to 500 pg/ml at 3 to 6 days postinfection. After 10 days, virus production was undetectable but could be stimulated by the addition of tumor necrosis factor alpha (TNF-alpha). To bypass limitations to receptor entry, we compared the fate of infection in these cell populations by transfection with the infectious HIV-1 clone, pNL4-3. Again, transfected progenitors and astrocytes produced virus for 7 days but diminished to low levels beyond 8 days posttransfection. During the nonproductive phase, TNF-alpha stimulated virus production from progenitors as late as 5 weeks posttransfection. Astrocytes produced 5- to 20-fold more infectious virus (27 ng of p24/10(6) cells) than progenitors at the peak of 3 days posttransfection. Differentiation of infected progenitors toward an astrocyte phenotype increased virus production to levels consistent with infected astrocytes, suggesting a phenotypic difference in viral replication. Using this cell culture system of multipotential human brain-derived progenitor cells, we provide evidence that progenitor cells may be a reservoir for HIV-1 in the brains of AIDS patients.

Astrocytes↗

PubMed2004

JC virus induces nonapoptotic cell death of human central nervous system progenitor cell-derived astrocytes.

JC virus (JCV), a human neurotropic polyomavirus, demonstrates a selective glial cell tropism that causes cell death through lytic infection. Whether these cells die via apoptosis or necrosis following infection with JCV remains unclear. To investigate the mechanism of virus-induced cell death, we used a human central nervous system progenitor-derived astrocyte cell culture model developed in our laboratory. Using in situ DNA hybridization, immunocytochemistry, electron microscopy, and an RNase protection assay, we observed that astrocytes support a progressive JCV infection, which eventually leads to nonapoptotic cell death. Infected astrocyte cell cultures showed no difference from noninfected cells in mRNA expression of the caspase family genes or in any ultrastructural features associated with apoptosis. Infected cells demonstrated striking necrotic features such as cytoplasmic vacuolization, watery cytoplasm, and dissolution of organelles. Furthermore, staining for caspase-3 and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling were not detected in infected astrocyte cultures. Our findings suggest that JCV-induced cell death of these progenitor cell-derived astrocytes does not utilize an apoptosis pathway but exhibits a pattern of cell destruction consistent with necrotic cell death.

Astrocytes↗

PubMed2003

Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization.

The human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 has been implicated in the pathogenesis of HIV-1 dementia. Thus, inhibition of gp120 activity could reduce HIV toxicity in the brain. We have used primary cultures of rat cerebellar granule cells to examine mechanisms whereby gp120 causes cell death and to characterize neuroprotective agents. gp120 induced a time- and concentration-dependent apoptotic cell death, which was caspase-3-mediated but caspase-1 independent, and was totally blocked by the irreversible caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone. Caspase-3 activation was observed only in neurons that internalize gp120, indicating that internalization is key to gp120 toxicity. Because brain-derived neurotrophic factor (BDNF) prevents caspase-3-mediated neuronal cell death, we examined whether BDNF could prevent gp120-mediated apoptosis. Preincubation of neurons with BDNF before the addition of gp120 reduced caspase-3 activation, and consequently rescued 80% of neurons from apoptosis. Most importantly, BDNF reduced the levels of CXC chemokine receptor-4 (CXCR4), a receptor that mediates HIV-1 gp120-induced apoptosis. This effect correlated with the ability of BDNF to reduce gp120 internalization and apoptosis. Moreover, BDNF blocked the neurotoxic effect of stromal-derived factor-1alpha, a natural ligand for CXCR4, further establishing a correlation between neuroprotection and downregulation of CXCR4. We propose that BDNF may be a valid therapy to slow down the progression of HIV/gp120-mediated neurotoxicity.

Animals↗