Natalizumab inhibits the expression of human endogenous retroviruses of the W family in multiple sclerosis patients: a longitudinal cohort study.

BACKGROUND: Several viruses were reported as co-factors triggering the pathogenesis of multiple sclerosis (MS), including the endogenous retroviruses of the HERV-W family, that were also proposed as biomarkers of disease progression and therapy outcome. OBJECTIVE: The objective of this article is to clarify whether in MS patients treatment with natalizumab has effects on MSRV/syncytin-1/HERV-W expression and the possible relationship with disease outcome. METHODS: Peripheral blood mononuclear cells were collected from 22 patients with relapsing-remitting disease, at entry and after three, six and 12 months of treatment with natalizumab. The cell subpopulations and the expression of MSRVenv/syncytin-1/HERV-Wenv were analyzed by flow cytometry and by discriminatory env-specific RT-PCR assays. RESULTS: By flow cytometry the relative amounts of T, NK and monocyte subpopulations were shown to remain fairly constant. A relative increase of B lymphocytes was observed at three to six months (p = 0.033). The MSRVenv and syncitin-1 transcripts were reduced at six to 12 months of therapy (p = 0.0001). Accordingly, at month 12, the plasma-membrane levels of the HERV-Wenv protein were reduced (p = 0.0001). B cells, NK and monocytes but not T cells expressed the HERV-Wenv protein. None of the patients relapsed during therapy. CONCLUSION: Effective therapy with natalizumab downregulates MSRV/syncytin-1/HERV-W expression.

Type III and I interferons increase HIV uptake and replication in human cells that overexpress CD4, CCR5, and CXCR4.

The newly discovered type III interferon lambda (IFN-lambda) has antiviral activity against a broad spectrum of viruses and potent immune-related activities. Its major producers are peripheral blood mononuclear cells (PBMCs) and dendritic cells. The above functions and cells are deeply involved in AIDS pathogenesis, but there is no information so far on IFN-lambda effects on HIV. Therefore we addressed the sensitivity of HIV-1 replication to cell exposure to human IFN-lambda2. Human PBMCs and C8166 T cells were treated with human Type III or Type I IFNs, and the ability of HIV-1 to bind and replicate in untreated and IFN-treated cells was investigated. Virus amounts were quantified by infectivity and p24 assays. In parallel, we evaluated the possible antiproliferative effects of IFN-lambda2 and the expression of CD4, CXCR4, and CCR5 genes, whose transcripts were quantified by real time RT-PCR. Data showed increased adsorption of HIV to IFN-treated cells in a dose-dependent fashion. Virus yields increased accordingly. In both systems the accumulation of CD4, CXCR4, and CCR5 transcripts was increased, particularly in PBMCs. Antiproliferative activity and classical antiviral state were instead detected on PBMCs, but not on C8166 cells. We concluded that pretreatment of PBMCs and C8166 cells with Type III and Type I IFNs causes increased HIV binding and replication. These effects are likely to be due to increased expression of HIV receptors and coreceptors on the plasma membrane. These findings indicate another mechanism utilized by HIV for subversion of host defenses.

HIV Tat acts on endogenous retroviruses of the W family and this occurs via Toll-like receptor 4: inference for neuroAIDS.

OBJECTIVE: The objective of this study is to verify whether HIV activates two endogenous retroviruses of the human endogenous retrovirus (HERV)-W family, multiple sclerosis-associated retrovirus (MSRV) and Syncytin-1, whose neuropathogenic and immunopathogenic properties could contribute to HIV-related neurodegeneration. DESIGN AND METHODS: Peripheral blood mononuclear cells, monocyte-macrophages and astrocytes were either infected by HIV or exposed to HIV-Tat, and/or other treatments. The expression of transcripts and proteins of interest was evaluated by real-time RT-PCR and western blotting assays, respectively. RESULTS: HIV and Tat increase the levels of MSRVenv mRNAs and HERV-Wenv proteins in astrocytes and in blood cells. In monocyte-macrophages, Tat also induces high levels of CCR2, CD16 and Toll-like receptor 4 (TLR4) molecules. Syncytin-1 response to Tat depends on the cell context: in monocytes, Tat stimulates MSRVenv and inhibits Syncytin-1, while in differentiated macrophages, it stimulates both elements. In primary astrocytes, Tat stimulates MSRV and Syncytin-1 indirectly, through interaction with TLR4 and induction of tumour necrosis factor-alpha (TNFα), without internalization. CONCLUSION: In-vivo consequence of the study could be that, through increase of CD16 and CCR2, Tat promotes neuroinvasion not only by HIV-infected monocytes/macrophages but also by the HERV-Ws, with their neuropathogenic potential. Also, the novel finding of TLR4 stimulation by Tat may be of relevance, as TLR4 is critical in neuroinflammation. Within central nervous system (CNS), Tat-induced TNFα could induce high levels of the HERV-Ws, in both macrophages and astrocytes, also without HIV replication. The indirect mechanism by which Tat activates the HERV-Ws through induction of TNFα could add a new piece to the puzzle of CNS pathogenesis, that is the HERV-Wenv contribute to the HIV-related neurodegeneration.

Activation of MSRV-type endogenous retroviruses during infectious mononucleosis and Epstein-Barr virus latency: the missing link with multiple sclerosis?

The etiology of multiple sclerosis (MS) is still unclear. The immuno-pathogenic phenomena leading to neurodegeneration are thought to be triggered by environmental (viral?) factors operating on predisposing genetic backgrounds. Among the proposed co-factors are the Epstein Barr virus (EBV), and the potentially neuropathogenic HERV-W/MSRV/Syncytin-1 endogenous retroviruses. The ascertained links between EBV and MS are history of late primary infection, possibly leading to infectious mononucleosis (IM), and high titers of pre-onset IgG against EBV nuclear antigens (anti-EBNA IgG). During MS, there is no evidence of MS-specific EBV expression, while a continuous expression of HERV-Ws occurs, paralleling disease behaviour. We found repeatedly extracellular HERV-W/MSRV and MSRV-specific mRNA sequences in MS patients (in blood, spinal fluid, and brain samples), and MRSV presence/load strikingly paralleled MS stages and active/remission phases. Aim of the study was to verify whether HERV-W might be activated in vivo, in hospitalized young adults with IM symptoms, that were analyzed with respect to expression of HERV-W/MSRV transcripts and proteins. Healthy controls were either EBV-negative or latently EBV-infected with/without high titers of anti-EBNA-1 IgG. The results show that activation of HERV-W/MSRV occurs in blood mononuclear cells of IM patients (2Log10 increase of MSRV-type env mRNA accumulation with respect to EBV-negative controls). When healthy controls are stratified for previous EBV infection (high and low, or no anti-EBNA-1 IgG titers), a direct correlation occurs with MSRV mRNA accumulation. Flow cytometry data show increased percentages of cells exposing surface HERV-Wenv protein, that occur differently in specific cell subsets, and in acute disease and past infection. Thus, the data indicate that the two main links between EBV and MS (IM and high anti-EBNA-1-IgG titers) are paralleled by activation of the potentially neuropathogenic HERV-W/MSRV. These novel findings suggest HERV-W/MSRV activation as the missing link between EBV and MS, and may open new avenues of intervention.

Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.

BACKGROUND: Proposed co-factors triggering the pathogenesis of multiple sclerosis (MS) are the Epstein Barr virus (EBV), and the potentially neuropathogenic MSRV (MS-associated retrovirus) and syncytin-1, of the W family of human endogenous retroviruses. METHODOLOGY/PRINCIPAL FINDINGS: In search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350), was studied on peripheral blood mononuclear cells (PBMC) from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT-PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV-W/MSRV/syncytin-1, with requirement of the NF-κB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines. CONCLUSIONS/SIGNIFICANCE: In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as initial trigger of future MS, years later, and HERV-W/MSRV/syncytin-1 as actual contributor to MS pathogenicity, in striking parallelism with disease behaviour.