Opportunistic Brain Infection Research Articles

Relapsing meningitis and limbic encephalitis in anti-AQP4-Ab-associated neuromyelitis optica spectrum disorder.

neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD.

Long-term outcome of natalizumab-associated progressive multifocal leukoencephalopathy in Austria: a nationwide retrospective study

Background/objectiveThe use of natalizumab (NAT) in multiple sclerosis (MS) may be complicated by progressive multifocal leukoencephalopathy (PML), a rare and life-threatening opportunistic brain infection. We aimed to analyze the course of MS after PML recovery together with the long-term outcome of NAT-associated PML (NAT-PML) in Austria.MethodsRetrospective study based on identification of cases in the nationwide Austrian MS treatment registry (AMSTR) and MS centers with review of patient records. The expanded disability status scale (EDSS) was used to measure neurological disability and outcome.ResultsAs of December 2022, we identified 15 NAT-PML cases in Austria; only 20% occurred after 2016, when increased vigilance commenced. Two patients did not survive acute PML, and an additional patient died five years later, yielding a mortality rate of 20%. Seizures occurred exclusively in patients with pronounced EDSS increase. Gadolinium (Gd)-enhancement on brain magnetic resonance imaging (MRI) on PML suspicion was associated with minor changes of post-PML neurological disability. Long-term follow-up of up to 132 months (median 76 months) was available in 11/15. The overall median EDSS increased from 3.5 at pre-PML to 6.5 at the last assessment. Regarding inflammatory MS-related disease activity during the observation period, one single individual experienced an MS relapse and another patient had two Gd-enhancing brain lesions. Three patients converted to progressive MS within three years from PML and the EDSS further increased in 6/11.ConclusionsThe number of NAT-PML cases is decreasing over time. While many patients accumulated severe persistent neurological deficits compared to pre-PML, inflammatory MS-related disease activity after PML recovery was rare.

Cerebral Toxoplasmosis in a Previously Fit Individual – Pitfalls in Management – A Case Report.

Most people with toxoplasmosis infection are asymptomatic. Cerebral toxoplasmosis in HIV patient represents poor prognostic determinant, but treatable if early treatment is initiated. A case of delayed diagnosis of cerebral toxoplasmosis is presented. A 27-year-old man presented with one-sided facial numbness and treated as Bell’s Palsy. Later he developed slurred speech. Contrast enhanced CT brain showed left frontal temporal hypodense lesion, leptomeningeal enhancement and perilesional oedema. Steroid was started. Four days later, he presented with decreased responsiveness. Retroviral was detected and diagnosis changed to opportunistic brain infection. He died after 3 days. Toxoplasmosis IgG antibodies turned out positive. In diagnosing cerebral toxoplasmosis, clinical presentation and examination are as important as laboratory testing and radiological imaging.

Infectious issues of therapeutic monoclonal antibodies in multiple sclerosis and neuromyelitis optica spectrum disorders

AbstractVarious effective monoclonal antibodies (mAbs) have been approved for both multiple sclerosis (MS) and anti‐aquaporin‐4‐seropositive neuromyelitis optica spectrum disorders worldwide, including in Japan. As these newer mAbs have distinct modes of action that effectively suppress the recurrence of inflammation and slow disability progression, they can modulate and interfere with the protective immune response against pathogens, resulting in various infectious complications. Among various mAbs, natalizumab (NTZ) has the highest risk of causing progressive multifocal leukoencephalopathy (PML), a rare but fatal opportunistic brain infection caused by John Cunningham polyomavirus. Switching from NTZ to B‐cell‐depleting mAbs, such as ocrelizumab, is also a possible risk factor for PML development. Alemtuzumab carries the risk of reactivation of varicella‐zoster virus (VZV); therefore, prophylactic acyclovir treatment is required. NTZ has also been associated with VZV reactivation. Eculizumab can cause severe meningococcal infection due to Neisseria meningitis, and vaccination prior to treatment induction is required. Attention to the reactivation of hepatitis B or Mycobacterium tuberculosis is also needed during mAb therapy. Additionally, in the era of severe acute respiratory syndrome coronavirus 2 infection (COVID‐19), the risk for of developing severe COVID‐19 may be associated with some mAbs, such as B‐cell‐depleting agents. Thorough understanding and mitigation strategies for infectious risks are essential.

PD-1-inhibitor pembrolizumab for treatment of progressive multifocal leukoencephalopathy.

The reactivation of human JC polyoma virus (JCPyV) results in lytic infection of oligodendrocytes and neuronal cells. The corresponding clinical picture is called progressive multifocal leukoencephalopathy (PML) and results mostly from a disease-related or drug-induced immunosuppression. The opportunistic brain infection leads to a progressive demyelination of multiple areas of the central nervous system. Patients can present with various neurological deficits ranging from slight motoric symptoms to marked aphasia or reduced vigilance. Currently, there is no effective causal therapy for PML. Survival depends on the ability to achieve timely immune reconstitution. If the immune system cannot be restored, PML progresses rapidly and often ends fatally within months. Recently, some evidence for positive response has been reported in patients treated with immune checkpoint inhibitor therapy. Here, we provide a case series of three PML patients with underlying hematological malignancies who were treated with anti-PD-1-antibody pembrolizumab at Hannover Medical School. All patients received an extensive diagnostic follow-up including cerebrospinal fluid analysis, brain imaging, and lymphocyte-phenotyping via flow cytometry. Our patients had very different outcomes, with the only patient showing a specific anti-JCPyV immune response in the sense of an increased JCPyV antibody index clearly benefiting most from the treatment. Our results partly support the hypothesis that anti-PD-1 therapy may represent a promising treatment option for patients with PML. However, there is a current lack of pre-therapeutic stratification regarding the therapeutic response rates. Before larger studies can be initiated to further evaluate the efficacy of anti-PD-1 antibodies in PML, it is imperative to develop a reliable strategy for selecting suitable patients.

Progressive multifocal leukoencephalopathy lesion and brain parenchymal segmentation from MRI using serial deep convolutional neural networks

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the JC virus and associated with substantial morbidity and mortality. Accurate MRI assessment of PML lesion burden and brain parenchymal atrophy is of decisive value in monitoring the disease course and response to therapy. However, there are currently no validated automatic methods for quantification of PML lesion burden or associated parenchymal volume loss. Furthermore, manual brain or lesion delineations can be tedious, require the use of valuable time resources by radiologists or trained experts, and are often subjective. In this work, we introduce JCnet (named after the causative viral agent), an end-to-end, fully automated method for brain parenchymal and lesion segmentation in PML using consecutive 3D patch-based convolutional neural networks. The network architecture consists of multi-view feature pyramid networks with hierarchical residual learning blocks containing embedded batch normalization and nonlinear activation functions. The feature maps across the bottom-up and top-down pathways of the feature pyramids are merged, and an output probability membership generated through convolutional pathways, thus rendering the method fully convolutional. Our results show that this approach outperforms and improves longitudinal consistency compared to conventional, state-of-the-art methods of healthy brain and multiple sclerosis lesion segmentation, utilized here as comparators given the lack of available methods validated for use in PML. The ability to produce robust and accurate automated measures of brain atrophy and lesion segmentation in PML is not only valuable clinically but holds promise toward including standardized quantitative MRI measures in clinical trials of targeted therapies. Code is available at: https://github.com/omarallouz/JCnet.

Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy

BackgroundProgressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection that is caused by the JC virus and is typically fatal unless immune function can be restored. Programmed cell death protein 1 (PD-1) is a negative regulator of the immune response that may contribute to impaired viral clearance. Whether PD-1 blockade with pembrolizumab could reinvigorate anti–JC virus immune activity in patients with PML was unknown.MethodsWe administered pembrolizumab at a dose of 2 mg per kilogram of body weight every 4 to 6 weeks to eight adults with PML, each with a different underlying predisposing condition. Each patient received at least one dose but no more than three doses.ResultsPembrolizumab induced down-regulation of PD-1 expression on lymphocytes in peripheral blood and in cerebrospinal fluid (CSF) in all eight patients. Five patients had clinical improvement or stabilization of PML accompanied by a reduction in the JC viral load in the CSF and an increase in in vitro CD4+ and CD8+ anti–JC virus activity. In the other three patients, no meaningful change was observed in the viral load or in the magnitude of antiviral cellular immune response, and there was no clinical improvement.ConclusionsOur findings are consistent with the hypothesis that in some patients with PML, pembrolizumab reduces JC viral load and increases CD4+ and CD8+ activity against the JC virus; clinical improvement or stabilization occurred in five of the eight patients who received pembrolizumab. Further study of immune checkpoint inhibitors in the treatment of PML is warranted. (Funded by the National Institutes of Health.)

Assessing understanding of individual risk and symptoms of progressive multifocal leukoencephalopathy in patients prescribed natalizumab for multiple sclerosis.

Natalizumab, a monoclonal antibody directed against α4 integrin, is a highly efficacious treatment commonly used in relapsing remitting multiple sclerosis. Natalizumab is associated with the potentially fatal, rare, demyelinating, opportunistic brain infection, progressive multifocal leukoencephalopathy (PML). Prognosis and disability from PML are determined by early diagnosis. Written tools are mandated in Australia and other prescribing countries with the aim to help patients understand the risks associated with treatment and ensure familiarity with the early symptoms of PML. We aimed to assess if these tools achieve such an outcome. A cross-sectional survey was conducted using a convenience sample of multiple sclerosis patients prescribed natalizumab presenting to the infusion centre at a major tertiary hospital. Patients were offered a multi-choice questionnaire to assess their knowledge on the treatment risks and surveillance requirements of their therapy. Three specific questions were highlighted by the researchers as crucial to patient understanding of PML and defined as basic knowledge. A total of 48 patients in our hospital was prescribed natalizumab; 37 responded. A total of 16 (43.2%) patients answered all three basic knowledge questions correctly. There was no difference in the ability to answer these questions based on length of treatment or co-ownership knowledge between patients with base knowledge and without. Natalizumab is associated with an increased risk of PML. Early detection and treatment of PML results in improved patient outcomes. Patient knowledge and co-partnership in the utilisation of PML risk tools is relevant in ensuring early detection. Our findings question the ability of currently sanctioned tools to inform patients of basic knowledge of PML and their risk of developing PML. A future study with a repetitive education approach and repeating the questionnaire at multiple time points would be of interest.

Differences in T cell cytotoxicity and cell death mechanisms between progressive multifocal leukoencephalopathy, herpes simplex virus encephalitis and cytomegalovirus encephalitis

During the appearance of human immunodeficiency virus infection in the 1980 and the 1990s, progressive multifocal leukoencephalopathy (PML), a viral encephalitis induced by the JC virus, was the leading opportunistic brain infection. As a result of the use of modern immunomodulatory compounds such as Natalizumab and Rituximab, the number of patients with PML is once again increasing. Despite the presence of PML over decades, little is known regarding the mechanisms leading to death of infected cells and the role the immune system plays in this process. Here we compared the presence of inflammatory T cells and the targeting of infected cells by cytotoxic T cells in PML, herpes simplex virus encephalitis (HSVE) and cytomegalovirus encephalitis (CMVE). In addition, we analyzed cell death mechanisms in infected cells in these encephalitides. Our results show that large numbers of inflammatory cytotoxic T cells are present in PML lesions. Whereas in HSVE and CMVE, single or multiple appositions of CD8+ or granzyme-B+ T cells to infected cells are found, in PML such appositions are significantly less apparent. Analysis of apoptotic pathways by markers such as activated caspase-3, caspase-6, poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF) showed upregulation of caspase-3 and loss of caspase-6 from mitochondria in CMVE and HSVE infected cells. Infected oligodendrocytes in PML did not upregulate activated caspase-3 but instead showed translocation of PARP-1 from nucleus to cytoplasm and AIF from mitochondria to nucleus. These findings suggest that in HSVE and CMVE, cells die by caspase-mediated apoptosis induced by cytotoxic T cells. In PML, on the other hand, infected cells are not eliminated by the immune system but seem to die by virus-induced PARP and AIF translocation in a type of cell death defined as parthanatos.

T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

BackgroundHighly active antiretroviral therapy (HAART) restores inflammatory immune responses in AIDS patients which may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. In resource-poor settings, 25% of patients receiving HAART may develop CNS-related immune reconstitution inflammatory syndrome (IRIS). Here we describe a reliable mouse model to study underlying immunopathological mechanisms of CNS-IRIS.MethodsUtilizing our HSV brain infection model and mice with MAIDS, we investigated the effect of immune reconstitution on MAIDS mice harboring opportunistic viral brain infection. Using multi-color flow cytometry, we quantitatively measured the cellular infiltrate and microglial activation.ResultsInfection with the LP-BM5 retroviral mixture was found to confer susceptibility to herpes simplex virus (HSV)-1 brain infection to normally-resistant C57BL/6 mice. Increased susceptibility to brain infection was due to severe immunodeficiency at 8 wks p.i. and a marked increase in programmed death-1 (PD-1) expression on CD4+ and CD8+ T-cells. Both T-cell loss and opportunistic brain infection were associated with high level PD-1 expression because PD-1-knockout mice infected with LP-BM5 did not exhibit lymphopenia and retained resistance to HSV-1. In addition, HSV-infection of MAIDS mice stimulated peripheral immune cell infiltration into the brain and its ensuing microglial activation. Interestingly, while opportunistic herpes virus brain infection of C57BL/6 MAIDS mice was not itself lethal, when T-cell immunity was reconstituted through adoptive transfer of virus-specific CD3+ T-cells, it resulted in significant mortality among recipients. This immune reconstitution-induced mortality was associated with exacerbated neuroinflammation, as determined by MHC class II expression on resident microglia and elevated levels of Th1 cytokines in the brain.ConclusionsTaken together, these results indicate development of an immune reconstitution disease within the central nervous system (CNS-IRD). Experimental immune reconstitution disease of the CNS using T-cell repopulation of lymphopenic murine hosts harboring opportunistic brain infections may help elucidate neuroimmunoregulatory networks that produce CNS-IRIS in patients initiating HAART.

Updated Incidence of Progressive Multifocal Leukoencephalopathy in Natalizumab-Treated Multiple Sclerosis Patients Stratified by Established Risk Factors (S41.001)

Objective: To quantify progressive multifocal leukoencephalopathy (PML) risk in multiple sclerosis (MS) patients considering or receiving natalizumab using three risk factors: anti-JC virus (JCV) antibody positive serostatus, prior immunosuppressant use, and natalizumab treatment duration. Background PML, an opportunistic brain infection caused by JCV, occurs primarily in patients who are immunocompromised or have received immunomodulatory therapies, such as natalizumab. Anti-JCV antibody positive status, prior immunosuppressant use, and natalizumab treatment duration are PML risk factors in natalizumab-treated patients. Design/Methods: Data from natalizumab postmarketing sources and clinical studies were used to estimate PML incidence in natalizumab-treated MS patients by anti-JCV antibody status (positive or negative), prior immunosuppressant use (yes or no), and duration of natalizumab treatment (1–24 or 25–48 months). Results: As of September 2011, 159 PML cases were confirmed among 92,105 patients exposed to natalizumab in the postmarketing setting. PML risk was lowest in anti-JCV antibody negative patients (estimated at ≤0.10 per 1000 [95%CI:0–0.56] or ≤0.17 per 1000 [95%CI:0.00–0.94], assuming one hypothetical PML case testing anti-JCV antibody negative prior to diagnosis, and exposures ≥1 natalizumab dose or ≥18 natalizumab doses, respectively). PML risk was highest in patients with all three risk factors, anti-JCV antibody positive status, prior immunosuppressant use, and 25–48 months of natalizumab treatment (9.8 per 1000; 95%CI:7.0–13.4). Conclusions: This analysis, representing approximately 178,000 patient-years of natalizumab experience, demonstrates that discrete MS subpopulations can be identified at greater or lesser PML risk based upon the presence or absence of risk factors using an algorithm capable of discerning an approximate 100-fold difference in risk between the highest and lowest risk groups. The use of anti-JCV antibody status in this quantitative algorithm marks the first use of a safety biomarker for risk stratification to inform treatment decisions in MS. Studies are ongoing to further characterize the PML risks presented in this analysis. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Bloomgren has received personal compensation for activities with Biogen Idec as an employee. Dr. Richman has received personal compensation for activities with Biogen Idec as employees.Dr. Richman holds stock and/or options in Biogen Idec, which sponsored research in which Dr. Richman was involved as an investigator. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator. Dr. Subramanyam has received personal compensation for activities with Biogen Idec as an employee. Dr. Subramanyam holds stock and/or stock options in Biogen Idec. Dr. Natarajan has received personal compensation for activities with Biogen Idec as an employee. Dr. Lee has received personal compensation for activities with Biogen Idec as an employee. Dr. Plavina has received personal compensation for activities with Biogen Idec as an employee.Dr. Plavina holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Plavina was involved as an investigator. Dr. Scanlon has received personal compensation for activities with Biogen Idec as an employee. Dr. Sandrock has received personal compensation for activities with Biogen Idec as an employee. Dr. Sandrock holds stock and/or stock options in Biogen Idec. Dr. Bozic has received personal compensation for activities with Biogen Idec. Dr. Bozic holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Bozic was involved as an investigator. Dr. Bozic holds stock and/or stock options in Biogen Idec.

Novel Interventions with Favorable Resolution of Natalizumab-Induced Progressive Multifocal Leukoencephalopathy (PML) (P07.062)

Objective: To describe the outcomes of early detected progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (NTMS) patients utilizing novel interventions. PML is an opportunistic brain infection caused by the JC virus (JCV) in NTMS patients. Background To address the need for effective approach to ameliorating PML. Design/Methods: Our empirical protocol for early diagnosis of PML in NTMS patients uses cranial MRIs at 4-6 month intervals or with new symptoms. Diagnosis was based on PML suspected MRI findings and positive JCV PCR in the CSF. Management consisted of plasma exchange, subcutaneous filgrastim 5 mg/kg/day (to restore lymphocyte adhesion capacity and immuno surveillance), oral maraviroc 150 mg twice daily (to modulate T cell recruitment), and oral mefloquin 300 mg/day and mirtazapine 50 mg/day (for their putative anti JCV effects). Patients were concurrently monitored using weekly contrast-MRIs and received intravenous corticosteroids upon emergence of immune reconstitution inflammatory syndrome (IRIS). Results: Six patients with NTMS were diagnosed with PML after 29-54 months of treatment. MRI discovered PML in two asymptomatic and two mildly symptomatic ones. Medications were well tolerated. Except for transient worsenings and seizures during IRIS, these patients did not significantly progress, remaining independent. Two of them already resumed employment, and the third one is soon expected to, as well. The two patients who were more severely symptomatic at diagnosis suffered intensified deficits, precluding independence. MS activity reoccurred in two patients after 6 and 8 months. Duration of post PML follow up 6-28 months. Conclusions: Our novel approach to PML in NTMS patients included monitoring that allowed very early diagnosis and administration of filgrastim and maraviroc, which likely contributed to the favorable clinical outcome in four patients. The two symptomatic at diagnosis patients remain incapacitated, though this regimen may have prevented fatal outcomes. The present interventions are of clinical significance and warrant further exploration. Disclosure: Dr. Stefoski has received personal compensation for activities with Biogen Idec, Acorda, Serono, Elan, and Teva Neuroscience. Dr. Stefoski has received royalty payments from Acorda Therapeutics. Dr. Stefoski has received research support from Biogen Idec, Novartis, Serono, and Pfizer. Dr. Ko has received personal compensation for activities with Biogen Idec, Serono, Inc., and Teva Neuroscience for consulting services. Dr. Javed has received personal compensation for activities with Teva Neuroscience, Bayer Pharmaceuticals, Serono, Inc., Novartis, Questcor and Biogen Idec as a consultant and/or speaker. Dr. Balabanov has received personal compensation for activities with Biogen Idec, Teva Neuroscience and Genzyme as a consultant, and speaker bureau honoraria from Biogen Idec and Teva Neuroscience.Dr. Balabanov has received research support from Biogen Idec.

Early years of biological agents therapy in Crohn's disease and risk of the human polyomavirus JC reactivation

Although the remarkable efficacy of biological therapy has resulted in significant success in inflammatory bowel disease (IBD) management, susceptibility to infections remains a concern. The biological agents include the tumor necrosis factor-alpha (TNF-alpha) inhibitors, for instance infliximab, and other immunomodulating agents, such as natalizumab. Progressive multifocal leukoencephalopathy (PML), a rare but mostly fatal opportunistic brain infection caused by reactivation of the human polyomavirus JC virus (JCV), has been found in two patients with multiple sclerosis and one patient with Crohn's disease (CD), linked to treatment with natalizumab. After these cases of PML, the commercial and investigational use of natalizumab was suspended in February 2005 but was subsequently resumed for multiple sclerosis and for CD, only through a special restricted distribution program. This review, starting from an extensive literature search by the PubMed database, resumes the clinical aspects and pathophysiology of CD and focuses on the biologics in current use in CD (infliximab, adalimumab, and natalizumab), in order to provide a reference and gateway to prevention, recognition, and management of JCV, in the early years of biological agents therapy. It also proposed to provide an overview on the hypothetical mechanism of reactivation of JC virus related to the use of these drugs.

CNK/T‐cell brain lymphoma associated with Epstein‐Barr virus in a patient with AIDS

We report a case of extranodal NK/T-cell lymphoma, nasal type, with exclusive cerebral localization in a patient with AIDS. The patient presented with neurological alterations, fever and convulsions, so the initial presumptive diagnosis was an opportunistic brain infection. MRI showed a left parietal necrotic lesion and a stereotactic brain biopsy was performed for pathological, microbiological and molecular studies. Histological sections showed an angiocentric and angiodestructive growth pattern and the immunophenotype of this tumor was CD56+, CD45+, CD3+ (cytoplasmic), Granzyme B+ and Perforin+. All the microbiological studies such as bacterial, fungi, micobacteria, Toxoplasma gondii and Cryptococcus determination were negatives. A PCR study with primer specific for EBV viral genome of Bam-Hi-w system was positive. Also, a rearrangement study showed T-cell gene rearrangement with monoclonal appearance. A diagnosis of extranodal NK/T-cell lymphoma was made and the patient died a few days later. This case represents a very rare example of NK/T-cell lymphoma of the brain in a patient with AIDS. The diagnosis of this kind of lymphomas requires a multimodality approach correlating clinical, morphological, immunophenotypic and molecular data.

Internalization of Exogenous Human Immunodeficiency Virus-1 Protein, Tat, by KG-1 Oligodendroglioma Cells Followed by Stimulation of DNA Replication Initiated at the JC Virus Origin

JC virus (JCV) is the etiological agent of an opportunistic brain infection, progressive multifocal leukoencephalopathy (PML), in AIDS. PML is fatal in approximately 4% of HIV-infected individuals, and although the overall incidence has fallen due to highly aggressive antiretroviral therapy (HAART), this percent has remained steady. It has been shown that the Tat protein of human immunodeficiency virus-1 (HIV-1) interacts in cells with cellular protein Puralpha. This interaction can stimulate transcription of both HIV-1 and JCV genes. HIV-1, however, infects primarily microglia and astrocytes in the brain, whereas JCV infects primarily oligodendrocytes. Although HIV-1 has been shown capable of infecting oligodendrocytes in vitro (Albright et al., 1996), no instance of viral coinfection of such cells with JCV has been reported. Tat is known to be secreted from cells in which it is made. Here we ask whether such exogenous Tat can influence JCV replication in oligodendrocytes. We find that glial cells infected with either HIV-1 or JCV are in proximity at the outer edge of PML lesions. Exogenous Tat is avidly incorporated into cultured KG-1 oligodendroglioma cells over a 72-h period and is colocalized with endogenous Puralpha both nuclear and juxtanuclear. At concentrations in the medium well below the pM range, Tat stimulates several-fold the replication in vivo of DNA initiated at the JCV origin. These results define a pathway by which a protein made by HIV-1 can directly affect the course of infection by another disease-causing virus.