Reactivation Of Viral Replication Research Articles

In Vivo Evidence of Respiratory Syncytial Virus Persistence in a Subset of Pulmonary Dendritic Cells Following a Primary Infection.

Respiratory syncytial virus (RSV) causes annual epidemics of infections affecting the whole population. In vitro, it has been shown to infect and persist in human dendritic cells (DCs) for prolonged periods. Initially persistence is associated with low levels of replication before the virus becomes dormant. Reactivation of viral replication can be triggered many months later. Infection of DCs is likely to influence the host's ability to generate effective long-term memory responses. A well-established animal was utilized to confirm that RSV both infects and persists in pulmonary DCs in vivo. Mice were infected with a modified strain of RSV expressing red fluorescent protein (RSV-RFP) when replicating. Clinical symptoms of infection were monitored using weight change and inflammatory cell counts from bronchoalveolar lavage, which correlated with the RSV viral titer (quantitative polymerase chain reaction). Lung tissues were collected at 3, 5, 7, and 21 days postinfection (dpi) to assess leukocyte populations by flow cytometry. Clinical symptoms and RSV viral load peaked at 5 dpi. RSV-RFP was most prevalent in macrophages at 3 dpi and also observed in B cells and DCs. At 21 dpi, RSV-RFP remained evident in a subset of conventional DCs (CD103+CD11b+) even though both clinical symptoms and pulmonary inflammation had resolved. These results confirm that in this well-established mouse model, RSV persists in lung conventional DCs following resolution of the acute infection. Further work is required to explore whether the virus continues with low-level replication before becoming dormant in vivo, as has been described in vitro.

Safety considerations for withdrawal of nucleos(t)ide analogues in patients with chronic hepatitis B: First, do no harm.

Nucleos(t)ide analogues (NA) are widely used to treat hepatitis B virus (HBV) infection, but they cannot eradicate the virus and treatment duration can be lifelong if the endpoint is set at seroclearance of the hepatitis B surface antigen (HBsAg). As an alternative strategy, finite NA therapy without the prerequisite of HBsAg seroclearance has been proposed to allow treatment cessation in patients with sustained undetectable HBV viremia for two to three years. However, reactivation of viral replication almost always follows NA withdrawal. Whereas HBV reactivation might facilitate HBsAg seroclearance in some, it could lead to serious acute flare-ups in a certain proportion of patients. Occurrence and consequences of NA withdrawal flares are complicated with various factors involving the virus, host, and treatment. Accurate risk prediction for severe flares following NA cessation is essential to ensure patient safety. The risks of life-threatening flares in patients who discontinued NA according to the stopping rules of current guidelines or local reimbursement policies have recently been quantitatively estimated in large-scale studies, which also provided empirical evidence to help identify vulnerable patients at risk of devastating outcomes. Moreover, risk predictors were further explored and validated to hopefully aid in patient selection and management. In this narrative review with a focus on patient safety, we summarize and discuss current literature on the incidence of severe flares following NA cessation, risk stratification for candidate selection, rules of posttreatment monitoring, and indications for treatment resumption. We also share our thoughts on the limitations of existing knowledge and suggestions for future research.

Severe Acute Exacerbation After Cessation of Nucleos(t)ide Analog for Chronic Hepatitis B: A Real-World Study of Routine Practice

There is an ongoing debate as to whether patients with chronic hepatitis B (CHB) may discontinue nucleos(t)ide analogue (NA) therapy before seroclearance of hepatitis B surface antigen (HBsAg).1 Whereas treatment discontinuation may facilitate HBsAg seroclearance and avoid indefinite drug exposure,2 reactivation of viral replication almost always follows treatment cessation and frequently leads to clinical flares.3 In patients who encounter withdrawal flares, severe acute exacerbation (SAE) could occur with fatal consequences.4 Quantitative knowledge about the risk of SAE is imperative to inform the debate and also the practice.

HEPATITIS VACCINATION AND ANTIBODY STATUS AMONG U.S. ADULTS WITH INFLAMMATORY BOWEL DISEASE

It is difficult to predict when inflammatory bowel disease (IBD) patients will need to receive immunosuppressive therapy. The use of immunosuppressants increases the risks of opportunistic infection and re-activation of viral replication. Hepatitis A (HAV) and B (HBV) are still endemic in certain areas of the world, and the latter has the potential to induce fulminant hepatitis with hepatic failure in the immunocompromised. Thus, it is important to routinely screen IBD patients for hepatitis and recommend appropriate vaccinations for those who are seronegative for antibodies.

HEPATITIS VACCINATION AND ANTIBODY STATUS AMONG U.S. ADULTS WITH INFLAMMATORY BOWEL DISEASE

Abstract Background It is difficult to predict when inflammatory bowel disease (IBD) patients will need to receive immunosuppressive therapy. The use of immunosuppressants increases the risks of opportunistic infection and re-activation of viral replication. Hepatitis A (HAV) and B (HBV) are still endemic in certain areas of the world, and the latter has the potential to induce fulminant hepatitis with hepatic failure in the immunocompromised. Thus, it is important to routinely screen IBD patients for hepatitis and recommend appropriate vaccinations for those who are seronegative for antibodies. Methods We performed a retrospective analysis with data from the National Health and Nutrition Survey (NHANES) from 2009 to 2010. We identified participants who reported whether they were told by a doctor or other health professional that they have IBD. We excluded those who did not provide pertinent information and those who did not know their vaccination status. For the purpose of statistical analysis, vaccination status was stratified as either complete or incomplete. Complete vaccination for HAV was defined as at least 2 doses, and that for HBV was defined as 3 doses. Incomplete vaccination was defined as the aggregate of inadequate doses, no doses, and refusal. Results HAV vaccination data was available in 48 IBD and 4303 non-IBD participants. Complete HAV vaccination was 14.6% among IBD patients, compared to 26.4% for non-IBD participants (odds ratio [OR] 0.47; 95% confidence interval [CI], 0.21–1.06). There were 55 IBD and 4443 non-IBD participants with known anti-HAV antibody status, and seropositivity was similar for both groups (41.8% vs. 42.4%, p=0.93). HBV vaccination data was available in 50 IBD and 4349 non-IBD participants. Complete HBV vaccination was 26.0% among IBD participants, compared to 34.4% among non-IBD participants (OR 0.67; 95% CI, 0.35–1.26). The presence of anti-HBV surface antibody was reported in 58 IBD and 4666 non-IBD participants, and seropositivity in the IBD group was less than the non-IBD group (17.2% vs. 23.5%, p=0.26). Conclusion Patients with IBD have lower rates of hepatitis vaccination and lower seropositivity for hepatitis antibodies. The current American College of Gastroenterology guidelines recommend the assessment and completion of HBV vaccination schedule prior to initiating biologic therapy. The European Crohn’s and Colitis Organisation is stricter on the timing of these preemptive measures and recommends doing so at the time of IBD diagnosis. A small number of studies have suggested that seroconversion following vaccination may be reduced in IBD patients, but even so, the vaccination rates need to be improved greatly. To do so, gastroenterologists and primary care physicians should systematically educate IBD patients on the importance of hepatitis vaccination and recommend routine testing for seronegative patients.

Lenalidomide in Combination with Arsenic Trioxide: an Effective Therapy for Primary Effusion Lymphoma.

Primary effusion lymphoma (PEL) is a rare aggressive subset of non-Hodgkin B cell lymphoma. PEL is secondary to Kaposi sarcoma herpes virus (KSHV) and predominantly develops in serous cavities. Conventional chemotherapy remains the treatment of choice for PEL and yields high response rates with no significant comorbidities. Yet, chemotherapy often fails in achieving or maintaining long-term remission. Lenalidomide (Lena), an immunomodulatory drug, displayed some efficacy in the treatment of PEL. On the other hand, arsenic trioxide (ATO) in combination with other agents effectively treated a number of blood malignancies, including PEL. In this study, we present evidence that the combination of ATO/Lena significantly enhanced survival of PEL mice, decreased the volume of exacerbated ascites in the peritoneum, and reduced tumor infiltration in organs of treated animals. In ex vivo treated PEL cells, ATO/Lena decreased the proliferation and downregulated the expression of KSHV latent viral proteins. This was associated with decreased NF-κB activation, resulting in reactivation of viral replication, downregulation of interleukin-6 (IL-6) and IL-10, inhibition of vascular endothelial growth factor, and apoptosis. Our results elucidate the mechanism of action of ATO/Lena and present it as a promising targeted therapeutic modality in PEL management, which warrants further clinical investigation.

Human Cytomegalovirus miR-US5-2 Downregulation of GAB1 Regulates Cellular Proliferation and UL138 Expression through Modulation of Epidermal Growth Factor Receptor Signaling Pathways

Regulation of epidermal growth factor (EGF) receptor (EGFR) signaling is critical for the replication of human cytomegalovirus (HCMV) as well as latency and reactivation in CD34+ hematopoietic progenitor cells. HCMV microRNAs (miRNAs) provide a means to modulate the signaling activated by EGF through targeting components of the EGFR signaling pathways. Here, we demonstrate that HCMV miR-US5-2 directly downregulates the critical EGFR adaptor protein GAB1 that mediates activation and sustained signaling through the phosphatidylinositol 3-kinase (PI3K) and MEK/extracellular signal-regulated kinase (ERK) pathways and cellular proliferation in response to EGF. Expression of HCMV UL138 is regulated by the transcription factor early growth response gene 1 (EGR1) downstream of EGFR-induced MEK/ERK signaling. We show that by targeting GAB1 and attenuating MEK/ERK signaling, miR-US5-2 indirectly regulates EGR1 and UL138 expression, which implicates the miRNA in critical regulation of HCMV latency.IMPORTANCE Human cytomegalovirus (HCMV) causes significant disease in immunocompromised individuals, including transplant patients. HCMV establishes latency in hematopoietic stem cells in the bone marrow. The mechanisms governing latency and reactivation of viral replication are complex and not fully understood. HCMV-encoded miRNAs are small regulatory RNAs that reduce protein expression. In this study, we found that the HCMV miRNA miR-US5-2 targets the epidermal growth factor receptor (EGFR) adaptor protein GAB1 which directly affects downstream cellular signaling pathways activated by EGF. Consequently, miR-US5-2 blocks the EGF-mediated proliferation of human fibroblasts. Early growth response gene 1 (EGR1) is a transcription factor activated by EGFR signaling that regulates expression of HCMV UL138. We show that miR-US5-2 regulates UL138 expression through GAB1-mediated downregulation of the signaling pathways that lead to EGR1 expression. These data suggest that miR-US5-2, through downregulation of GAB1, could play a critical role during reactivation from latency by reducing proliferation and UL138 expression.

The effects of MAPK p38α on AZT resistance against reactivating HIV-1 replication in ACH2 cells.

Antiretroviral therapy (ART) has remarkably decreased HIV-related mortality. However, drug-resistant HIV variants pose a potential threat to the long-term success of ART. Both HIV mutants and host factors can cause HIV drug resistance. Using susceptible ACH2 cells chronically infected with HIV-1, we examined the effects of MAPK p38α on AZT resistance against reactivating HIV-1 replication that can be activated by HIV-1 superinfection. We found that HIV-1 superinfection induced more viral production, which was diminished by p38 inhibitor, SB203580, and by AZT in cells infected with non-AZT-resistant HIV-1 strain MN. p38α expression can resist action of AZT in inhibition of HIV-1 replication with increased expression of transcription factor, NF-ĸBp65, SP1, and c-Fos through activation of TCR-related pathways with upregulation of CD3, TCRα, TCRβ, Zap-70, PKC, PLCγ1, GRB2, and PI3K/Akt expression. In HIV-1 MN superinfection under AZT treatment, expression of p38α led to HIV vif expression and inhibited APOBEC3G expression. We also investigated effects of p38α on gp130/JAK-STAT pathways, in which p38α increased expression of protein, gp130, EGFR, Jak2, STAT1, STAT3, STAT5, ras, and TF. p38α could induce apoptotic pathways with upregulation of Fas, FADD, Caspase-8, p53, and Bax, and downregulation of Bcl2 expression. These results indicate that p38α plays a positive role in reactivation of viral replication from HIV-1 latent infection and leads to HIV-1 AZT resistance. In conclusion, MAPKp38α can activate HIV-1 replication inhibited by AZT from HIV-1 latent infection and may be used as a latency reversal agent. The activation involves induction of several cell signaling pathways that are required for HIV-1 replication, which may be integrated into future viral remission strategies.

Potential of Radiation-Induced Cellular Stress for Reactivation of Latent HIV-1 and Killing of Infected Cells.

The use of highly active antiretroviral therapy against HIV-1 for last two decades has reduced mortality of patients through extension of nonsymptomatic phase of infection. However, HIV-1 can be preserved in long-lived resting CD4(+) T cells, which form a viral reservoir in infected individuals, and potentially in macrophages and astrocytes. Reactivation of viral replication is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus (shock and kill strategy). In this opinion piece, we consider potential application of therapeutic doses of irradiation, the well-known and effective stress signal that induces DNA damage and activates cellular stress response, to resolve two problems: activate HIV-1 replication and virion production in persistent reservoirs under cART and deplete infected cells through selective cell killing using DNA damage responses.

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma.

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.

Bilaterale vaskularisierte disziforme Hornhautnarbe herpetischer Genese bei einem Kind

Bilateral keratitis is rare and can have various causes. For a good outcome after treatment, the correct diagnosis is decisive. A 15-year-old boy presented to our clinic with recurrent keratoconjunctivitis and progressive loss of vision in both eyes since 6 years. The best corrected visual acuity was 0.1 in the right eye and 1/12 in the left eye. Slit-lamp examination verified keratitis disciformis with strongly vascularized corneal stromal scars without conjunctival follicles on both sides. Based on the clinical diagnosis, antiviral treatment was initiated. Best corrected visual acuity 8 weeks later increased to 0.4 in the right eye and 0.8 in the left eye and the corneal edema decreased in both eyes. Due to noncompliance the patient returned with a perforated corneal ulcer of the left eye, where an á chaud penetrating keratoplasty had to be performed. Herpes simplex virus is one of the most common causes of keratitis and has different manifestations. In the treatment of keratitis disciformis the use of topical steroids is mandatory as there is an active immunological process. The use of systemic and local antiviral treatment is necessary at the same time in order to avoid reactivation of viral replication. Bilateral keratitis is relatively frequent in children. Herpetic keratitis is now well treatable if the various manifestations of the disease are recognized early and an appropriate therapy is adjusted accordingly.

Post-Transfusion Occult Hepatitis B (OBI): A Global Challenge for Blood Recipients and Health Authorities

: Hepatitis B is one of the most frequent post-transfusion infections. Occult hepatitis B infection (OBI) is a form of hepatitis B infection in which, despite the presence of HBV-DNA in the serum and hepatocytes of the carrier, HBsAg is absent. In addition to the risk of transmission through the transfusion of infected blood, reactivation of hepatitis B in OBI patients and recipients of their blood can lead to cirrhosis, hepatic cancer, and reactivation of viral replication in the carrier. Therefore, effective assays to assess and screen for OBI in blood donors are of paramount importance and require urgent attention. Recently, several investigations in various regions of Iran have reported OBI in blood donors. In response, there has been a drive to apply more specific, sensitive, and accurate methods for the detection of HBV, which should become an obligatory screening process for all blood transfusion services. In this review, we address the progression of occult hepatitis B and the common problems associated with occult hepatitis B worldwide. Finally, we reflect on the research and screening that is being performed in Iran to deal with this problem. Implication for health policy/practice/research/medical education:Occult HBV infection (OBI) is a potential risk factor for post transfusion hepatitis B. Based on recent reports, this review aims to present the current status of OBI prevalence among worldwide blood donors, common problems associated with OBI as well as useful tests for HBV screening. Please cite this paper as: Kazemi Arababadi M, Hassanshahi G, Pourfathollah AA, Rezazadeh Zarandi E, Kennedy D. Post-Transfusion Occult Hepatitis B (OBI): A Global Challenge for Blood Recipients and Health Authorities. Hepat Mon. 2011;11(9):714-8. DOI: 10.5812/kowsar. 1735143X.694 ©2011 Kowsar M.P.Co. All rights reserved.

Post-Transfusion Occult Hepatitis B (OBI): A Global Challenge for Blood Recipients and Health Authorities

Hepatitis B is one of the most frequent post-transfusion infections. Occult hepatitis B infection (OBI) is a form of hepatitis B infection in which, despite the presence of HBV-DNA in the serum and hepatocytes of the carrier, HBsAg is absent. In addition to the risk of transmission through the transfusion of infected blood, reactivation of hepatitis B in OBI patients and recipients of their blood can lead to cirrhosis, hepatic cancer, and reactivation of viral replication in the carrier. Therefore, effective assays to assess and screen for OBI in blood donors are of paramount importance and require urgent attention. Recently, several investigations in various regions of Iran have reported OBI in blood donors. In response, there has been a drive to apply more specific, sensitive, and accurate methods for the detection of HBV, which should become an obligatory screening process for all blood transfusion services. In this review, we address the progression of occult hepatitis B and the common problems associated with occult hepatitis B worldwide. Finally, we reflect on the research and screening that is being performed in Iran to deal with this problem.

The Characteristics of Hemorrhagic Cystitis After Allogeneic Stem Cell Transplantation, and Possible Predictive Value of Absolute Lymphocyte Count for Clinical Outcome.

AbstractAbstract 1284 Background;Hemorrhagic cystitis (HC) after allogeneic stem cell transplantation (SCT) is a common complication associated with frequent prolongation of hospitalization and occasional death and yet, the observed risk and prognostic factors as well as the understanding of pathophysiology remain inconsistent. Recent evidences point to HC being triggered by reactivation of viral replication, mainly BK virus, implicating factors standing for recipients' status of immunity may correlate with the incidence, severity and prognosis of HC. Methods;We retrospectively investigated 450 adult patients who underwent allogeneic SCT from January 2007 through December 2009 in order to analyze the incidence, risk and prognostic factors of HC. Results;The median age was 38 years old (range, 15–70) and 90 % of the patients had malignant disease. Thirty-five percent of patient (n=159) had advanced disease status at transplantation. Two hundred thirty-nine patients (53%) and 211 (47%) had related and unrelated donors, respectively. Conditioning regimens consisted of myeloablative (n=266, 59%) and reduced-intensity regimens (n=184, 41%). With a median follow-up of 549 days (range, 83 – 1172), 58 patients developed HC (cumulative incidence, 13.2%±1.6%) and the median day of onset was 36 days after transplant (range, 1–441) consisting of pre-engraft (n=13) and post-engraft HC (n=45). Among 58 patients with HC, urine virus was detected in 54 patients. Thirty patients had positive PCR for BK virus and 19 patients were positive by JC virus PCR. Not all the patients with positive PCR results showed growth by urine culture. Eleven patients were BK virus culture positive and 7 patients showed growth of adenovirus. Four patients showed positive PCR results for both BK virus and JC virus. The overall severity of HC was as follows; grade I (19%), grade II (21%), grade III (47%), and grade IV (14%). On multivariate analyses, advanced disease status at transplantation [HR (95% CI), 1.81 (1.003-3.266), P-value=0.049] and concurrent acute graft-versus-host disease (GVHD) [HR (95% CI), 1.88 (1.013-6.487), P-value=0.046] were revealed to be significantly associated with the occurrence of HC. All patients with HC were initially treated with forced hydration and/or bladder irrigation, and cidofovir at 5 mg/kg/day for two consecutive weeks and biweekly thereafter was used in 18 patients with documented test results associated with BK virus showing no improvement within 7 days after treatment. In 4 cases of grade IV HC with urinary tract obstruction, double-J catheterization or percutaneous nephrostomy were performed. The overall complete response (CR) rate of HC patients was 72%. Notably, multivariate analyses showed that patients with absolute lymphocyte count over 1000/μL at onset of HC had significantly better outcome in the achievement of CR [HR (95% CI), 10.8 (1.16-100.81), P-value=0.036)]. Conclusions;This study demonstrates the incidence, risk and prognostic factors of 58 patients with HC, and the value of the absolute lymphocyte count at onset of HC as a prognostic predictor. Patients who have advanced disease status at transplantation or develop acute GVHD are at high risk of developing HC, and early monitoring should be implemented. Our data also indicates that replication of JC virus as well as BK virus may account for a considerable portion of etiologies of HC. Prospective trials on analyzing the risk and prognostic factors for HC are needed for the development of reliable tools for predicting HC, and the relation between degree of immune reconstitution or JC virus and the occurrence of HC after SCT should also be further investigated. Disclosures:No relevant conflicts of interest to declare.

Reactivation of viral replication after replacement of tenofovir by adefovir

Reactivation of viral replication after replacement of tenofovir by adefovir

Hepatitis fulminante tras suspensión del tratamiento inmunosupresor en un paciente con hepatitis crónica por virus de la hepatitis B y C

We report a patient with chronic virus B and C hepatitis, who developed a fatal hepatic failure after chemotherapy suppression. A 56 years old man diagnosed of glioblastoma in treatment with cisplatin, procarbacin and UFT whose treatment was stopped because a raise in serum transaminases. Five days later, he developed an acute hepatic failure and died.Fulminant hepatitis is a known complication of immunosuppresive therapy withdrawal in patients with chronic virus B and virus C infection. It is accepted to be caused by the reactivation of viral replication during inmunosupressive therapy followed by hepatic necrosis with the restablishment of normal immunity.Management should include corticosteroid therapy and probably lamivudine, however the best way to face it is to prevent it measuring the viral DNA in patients with chronic hepatitis receiving chemotherapy.

Reactivation of viral replication after liver resection in patients infected with hepatitis B virus.

To investigate the mechanisms and risk factors underlying postoperative reactivation of hepatitis after liver resection for hepatitis B virus-related hepatocellular carcinoma. Although risk factors for acute hepatic failure after liver resection have been reported in patients with chronic liver disease, the issue of reactivation of hepatitis B virus replication after liver resection is unresolved. Fifty-five patients with hepatocellular carcinoma and hepatitis B surface antigen underwent liver resection. In 25 of these 55 patients, serum levels of hepatitis B virus DNA and the type of hepatitis B virus were determined before and after surgery. Postoperative hepatitis occurred in 13 of the 55 patients (24%). Reactivation of viral replication occurred after liver resection in 7 of the 25 patients tested, and alanine aminotransferase activity increased in 6 of these 7 patients. High preoperative alanine aminotransferase activity, high levels of hepatitis B virus DNA, presence of wild-type DNA, and detection of hepatitis B core antigen in hepatocytes, all features of the immune clearance phase in the natural course of hepatitis B virus infection with no surgery, were more likely to be found in patients with reactivation than in patients without reactivation. During the immune clearance phase of hepatitis B virus infection, especially the period of acute exacerbation, changes in serum hepatitis B virus DNA level should be monitored for early warnings of reactivation of viral replication, likely to cause severe postoperative hepatitis and acute hepatic failure.

The role of T-cell-mediated mechanisms in virus infections of the nervous system.

T lymphocytes play a decisive role in the course and clinical outcome of viral CNS infection. Summarizing the information presented in this review, the following sequence of events might occur during acute virus infection: After invasion of the host and a few initial rounds of replication, the virus reaches the CNS in most cases by hematogeneous spread. After passage through the BBB, CNS cells are infected and replication of virus in brain cells causes activation of the surrounding microglia population. Moreover, local production of IFN-alpha/beta induces expression of MHC antigens on CNS cells, and microglial cells start to phagocytose cellular debris, which accumulates as a result of virus-induced cytopathogenic effects. Upon phagocytosis, microglia becomes more activated; they up-regulate MHC molecules, acquire antigen presentation capabilities and secrete chemokines. This will initiate up-regulation of adhesion molecules on adjacent endothelial cells of the BBB. Transmigration of activated T lymphocytes through the BBB is followed by interaction with APC, presenting the appropriate peptides in the context of MHC antigens. It appears that CD8+ T lymphocytes are amongst the first mononuclear cells to arrive at the infected tissue. Without a doubt, their induction and attraction is deeply influenced by natural killer cells, which, after virus infection, secrete IFN-gamma, a cytokine that stimulates CD8+ T cells and diverts the immune response to a TH1-type CD4+ T cell-dominated response. Following the CD8+ T lymphocytes, tissue-penetrating, TH1 CD4+ T cells contact local APC. This results in a tremendous up-regulation of MHC molecules and secretion of more chemotactic and toxic substances. Consequently an increasing number of inflammatory cells, including macrophages/microglia and finally antibody-secreting plasma cells, are attracted to the site of virus infection. All trapped cells are mainly terminally differentiated cells that are going to enter apoptosis during or shortly after exerting their effector functions. The clinical consequences and the influence of the effector phase on the further course of the infection depends on the balance and fine-tuning of the contributing lymphoid cell populations. Generally, any delay in the recruitment of effector lymphocytes to the tissue or an unbalanced combination of lymphocyte subsets allows the virus to spread in the CNS, which in turn will cause severe immune-mediated tissue effects as well as disease. If either too late or partially deficient, the immune system response may contribute to a lethal outcome or cause autosensitization to brain-specific antigens by epitope spreading to the antigen-presenting system in peripheral lymphoid tissue. This could form the basis for subsequent booster reactions of autosensitized CD4+ T cells--a process that finally will end in an inflammatory autoimmune reaction, which in humans we call multiple sclerosis. In contrast, a rapid and specific local response in the brain tissue will result in efficient limitation of viral spread and thereby a subclinical immune system-mediated termination of the infection. After clearance of virus-infected cells, downsizing of the local response probably occurs via self-elimination of the contributing T cell populations and/or by so far unidentified signal pathways. However, much of this is highly speculative, and more data have to be collected to make decisive conclusions regarding this matter. Several strategies have been developed by viruses to escape T cell-mediated eradication, including interference with the MHC class I presentation pathway of the host cell or "hiding" in cells which lack MHC class I expression. This may result in life-long persistence of the virus in the brain, a state which probably is actively controlled by T lymphocytes. Under severe immunosuppression, however, reactivation of viral replication can occur, which is a lethal threat to the host.

Fulminant Hepatitis as a Consequence of Reactivation of Hepatitis B Virus Infection after Discontinuation of Low-Dose Methotrexate Therapy

Brief Reports1 March 1990Fulminant Hepatitis as a Consequence of Reactivation of Hepatitis B Virus Infection after Discontinuation of Low-Dose Methotrexate TherapyMichele A. Flowers, MD, Jenny Heathcote, MB, BS, MD, Ian R. Wanless, MD, Morris Sherman, MB, BCh, PhD, William J. Reynolds, MD, Ross G. Cameron, MD, PhD, Gary A. Levy, MD, Robert D. Inman, MDMichele A. Flowers, MDSearch for more papers by this author, Jenny Heathcote, MB, BS, MDSearch for more papers by this author, Ian R. Wanless, MDSearch for more papers by this author, Morris Sherman, MB, BCh, PhDSearch for more papers by this author, William J. Reynolds, MDSearch for more papers by this author, Ross G. Cameron, MD, PhDSearch for more papers by this author, Gary A. Levy, MDSearch for more papers by this author, Robert D. Inman, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-112-5-381 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptDevelopment of liver disease in chronic hepatitis B virus carriers depends on the interplay between viral products and the host immune system. Although it is generally believed that the virus itself is not cytopathic, most clinical studies document viral replication when the liver disease is progressive. In contrast, chronic carriers of hepatitis B virus who have lost the markers of viral replication usually have static or only slowly progressive liver disease. Reactivation of viral replication in such patients is often associated with an increase in the activity of liver disease. Both spontaneous reactivation and reactivation in association with drug therapy...

Reactivation of viral replication in anti‐HBe positive chronic HBsAg carriers

Reactivation of hepatitis B virus replication was investigated in an unselected group of 44 HBV DNA negative, anti-HBe positive chronic HBsAg carriers. Twenty-five patients (54%) were intravenous drug addicts and 7 (16%) were male homosexuals. Sixteen patients had evidence of delta infection and five of the seven male homosexuals had human immunodeficiency virus infection. The patients were followed for 1 to 180 months (median, 24 months) while HBV DNA negative, anti-HBe positive. Reactivation, defined as reappearance of HBV DNA or HBeAg, or both, was detected in six patients corresponding to an annual reactivation rate of 5%. Reactivation in four patients was detected by reversion to HBV DNA positivity only, whereas HBeAg/anti-HBe status remained unchanged. Two patients became both HBV DNA and HBeAg positive. None of the patients developed hepatitis-like symptoms and transaminase elevation was only observed in two patients. Reactivation in two patients was ascribed to human immunodeficiency virus infection and in one patient to chronic lymphatic leukaemia. It is concluded that HBV DNA seems to be superior to HBeAg in the detection of reactivation of HBV replication and that reactivation associated with clinical symptoms leading to progression in chronic liver disease is a rare event in the population studied.