Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies.

Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation's delicate balance, spanning innate and adaptive immunity. Viral factors' disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation's impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors: A case report and literature analysis.

Hepatitis B virus (HBV) reactivation (HBVr) represents a severe and potentially life-threatening condition, and preventive measures are available through blood test screening or prophylactic therapy administration. The assessment of HBVr traditionally considers factors such as HBV profile, including hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen, along with type of medication (chemotherapy; immunomodulants). Nevertheless, consideration of possible patient's underlying tumor and the specific malignancy type (solid or hematologic) plays a crucial role and needs to be assessed for decision-making process.

A macrophage-cell model of HIV latency reveals the unusual importance of the bromodomain axis.

BACKGROUND: Although macrophages are now recognized as an essential part of the HIV latent reservoir, whether and how viral latency is established and reactivated in these cell types is poorly understood. To understand the fundamental mechanisms of viral latency in macrophages, there is an urgent need to develop latency models amenable to genetic manipulations and screening for appropriate latency-reversing agents (LRAs). Given that differentiated THP-1 cells resemble monocyte-derived macrophages in HIV replication mechanisms, we set out to establish a macrophage cell model for HIV latency using THP-1 cells. METHODS: We created single-cell clones of THP-1 cells infected with a single copy of the dual-labeled HIVGKO in which a codon switched eGFP (csGFP) is under the control of the HIV-1 5' LTR promoter, and a monomeric Kusabira orange 2 (mKO2) under the control of cellular elongation factor one alpha promoter (EF1α). Latently infected cells are csGFP-, mKO2+, while cells with actively replicating HIV (or reactivated virus) are csGFP+,mKO2+. After sorting for latently infected cells, each of the THP-1 clones with unique integration sites for HIV was differentiated into macrophage-like cells with phorbol 12-myristate 13-acetate (PMA) and treated with established LRAs to stimulate HIV reactivation. Monocyte-derived macrophages (MDMs) harboring single copies of HIVGKO were used to confirm our findings. RESULTS: We obtained clones of THP-1 cells with latently infected HIV with unique integration sites. When the differentiated THP-1 or primary MDMs cells were treated with various LRAs, the bromodomain inhibitors JQ1 and I-BET151 were the most potent compounds. Knockdown of BRD4, the target of JQ1, resulted in increased reactivation, thus confirming the pharmacological effect. The DYRK1A inhibitor Harmine and lipopolysaccharide (LPS) also showed significant reactivation across all three MDM donors. Remarkably, LRAs like PMA/ionomycin, bryostatin-1, and histone deacetylase inhibitors known to potently reactivate latent HIV in CD4 + T cells showed little activity in macrophages. CONCLUSIONS: Our results indicate that this model could be used to screen for appropriate LRAs for macrophages and show that HIV latency and reactivation mechanisms in macrophages may be distinct from those of CD4 + T cells.

The cell biology of HIV-1 latency and rebound.

Transcriptionally latent forms of replication-competent proviruses, present primarily in a small subset of memory CD4+ T cells, pose the primary barrier to a cure for HIV-1 infection because they are the source of the viral rebound that almost inevitably follows the interruption of antiretroviral therapy. Over the last 30 years, many of the factors essential for initiating HIV-1 transcription have been identified in studies performed using transformed cell lines, such as the Jurkat T-cell model. However, as highlighted in this review, several poorly understood mechanisms still need to be elucidated, including the molecular basis for promoter-proximal pausing of the transcribing complex and the detailed mechanism of the delivery of P-TEFb from 7SK snRNP. Furthermore, the central paradox of HIV-1 transcription remains unsolved: how are the initial rounds of transcription achieved in the absence of Tat? A critical limitation of the transformed cell models is that they do not recapitulate the transitions between active effector cells and quiescent memory T cells. Therefore, investigation of the molecular mechanisms of HIV-1 latency reversal and LRA efficacy in a proper physiological context requires the utilization of primary cell models. Recent mechanistic studies of HIV-1 transcription using latently infected cells recovered from donors and ex vivo cellular models of viral latency have demonstrated that the primary blocks to HIV-1 transcription in memory CD4+ T cells are restrictive epigenetic features at the proviral promoter, the cytoplasmic sequestration of key transcription initiation factors such as NFAT and NF-κB, and the vanishingly low expression of the cellular transcription elongation factor P-TEFb. One of the foremost schemes to eliminate the residual reservoir is to deliberately reactivate latent HIV-1 proviruses to enable clearance of persisting latently infected cells-the "Shock and Kill" strategy. For "Shock and Kill" to become efficient, effective, non-toxic latency-reversing agents (LRAs) must be discovered. Since multiple restrictions limit viral reactivation in primary cells, understanding the T-cell signaling mechanisms that are essential for stimulating P-TEFb biogenesis, initiation factor activation, and reversing the proviral epigenetic restrictions have become a prerequisite for the development of more effective LRAs.

Transcriptome analysis of Burkitt lymphoma cells treated with anti-convulsant drugs that are inhibitors of Epstein-Barr virus lytic reactivation.

Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in cultured cells. Cell lines harboring latent EBV can be induced into the lytic cycle by treatment with chemical inducing agents. In the Burkitt lymphoma cell line HH514-16 the viral lytic cycle is triggered by butyrate, a histone deacetylase (HDAC) inhibitor. Butyrate also alters expression of thousands of cellular genes. However, valproic acid (VPA), another HDAC inhibitor with global effects on cellular gene expression blocks EBV lytic gene expression in Burkitt lymphoma cell lines. Valpromide (VPM), an amide derivative of VPA, is not an HDAC inhibitor, but like VPA blocks induction of the EBV lytic cycle. VPA and VPM are the first examples of inhibitors of initial stages of lytic reactivation. We compared the effects of VPA and VPM, alone and in combination with butyrate, on host cellular gene expression using whole transcriptome analysis (RNA-seq). Gene expression was analyzed 6 h after addition of the compounds, a time before the first EBV lytic transcripts are detected. The results address two alternative, yet possibly complementary, mechanisms for regulation of EBV lytic reactivation. First, cellular genes that were up- or down-regulated by butyrate, but no longer altered in the presence of VPA or VPM, represent genes that correlated with EBV lytic reactivation. Second, genes regulated similarly by VPA and VPM in the absence and presence of butyrate are candidates for suppressors of EBV reactivation. Two genes upregulated by the lytic cycle inhibitors, CHAC1 and SLC7A11, are related to redox status and the iron-dependent cell death pathway ferroptosis. This study generates new hypotheses for control of the latency to lytic cycle switch of EBV and provides the first description of effects of the anti-convulsant drug VPM on global human cellular gene expression.

[Clinical Study of Allogeneic Hematopoietic Stem Cell Transplantation Patients with Co-Reactivation of Cytomegalovirus and Epstein-Barr Virus].

OBJECTIVE: To explore the clinical characteristics and risk factors of cytomegalovirus(CMV) and Epstein-Barr virus(EBV) co-reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its influence on prognosis. METHODS: The clinical data of 222 patients who received allo-HSCT from January 2015 to December 2020 were collected, and the patients were divided into groups according to the occurrence of CMV and EBV infection. Kaplan-Meier method was used for survival analysis, and Cox proportional hazard regression model was used to analyze the risk factors of co-reactivation of CMV and EBV. RESULTS: After allo-HSCT, there were 30 patients with co-reactivation of CMV and EBV (CMV++EBV+ group), 101 patients with CMV viremia (CMV+ group), 149 patients with EBV viremia (EBV+ group), and 28 patients with CMV and EBV inactivation (CMV-+ EBV- group). Compared with the other groups, the incidence of acute graft-versus-host disease (aGVHD) and hemorrhagic cystitis (HC) was higher in CMV++ EBV+ groups (53.3% vs 42.6%, 36.9%, 17.9%, P < 0.001; 36.7% vs 32.7%, 22.8%, 10.7%, P =0.042). The incidence of post-transplant lymphoproliferative disease (PTLD) in CMV++ EBV+ group was similar to CMV+ group and EBV+ group (3.3% vs 3.0%, 3.4%, P =0.811). Univariate and multivariate analysis showed that the persistent time of CMV and EBV after transplantation were independent risk factors for co-reactivation of CMV and EBV. Compared with the other groups, the 2-year overall survival (OS) rate and 2-year disease-free survival (DFS) rate of patients in CMV++EBV+ group were lower (46.7% vs 74.9%, 83.4%, 71.4%, P < 0.001; 46.7% vs 70.9%, 79.5%, 69.9%, P =0.002), and 2-year non-recurrence mortality (NRM) was higher (48.2% vs 22%, 13.6%, 18.7%, P <0.001). CONCLUSION: The persistent time of CMV and EBV after transplantation are independent risk factors for patients with co-reactivation of CMV and EBV. Patients with co-reactivation of CMV and EBV had lower OS and DFS rate and higher NRM, suggesting that the clinical prognosis of the patients are worse.

Serious neurological adverse events in immunocompetent children and adolescents caused by viral reactivation in the years following varicella vaccination.

Serious adverse events following vaccination include medical complications that require hospitalisation. The live varicella vaccine that was approved by the Food and Drug Administration in the United States in 1995 has an excellent safety record. Since the vaccine is a live virus, adverse events are more common in immunocompromised children who are vaccinated inadvertently. This review includes only serious adverse events in children considered to be immunocompetent. The serious adverse event called varicella vaccine meningitis was first reported in a hospitalised immunocompetent child in 2008. When we carried out a literature search, we found 15 cases of immunocompetent children and adolescents with varicella vaccine meningitis; the median age was 11 years. Eight of the children had received two varicella vaccinations. Most of the children also had a concomitant herpes zoster rash, although three did not. The children lived in the United States, Greece, Germany, Switzerland, and Japan. During our literature search, we found five additional cases of serious neurological events in immunocompetent children; these included 4 cases of progressive herpes zoster and one case of acute retinitis. Pulses of enteral corticosteroids as well as a lack of herpes simplex virus antibody may be risk factors for reactivation in immunocompetent children. All 20 children with adverse events were treated with acyclovir and recovered; 19 were hospitalised and one child was managed as an outpatient. Even though the number of neurological adverse events remains exceedingly low following varicella vaccination, we recommend documentation of those caused by the vaccine virus.

Dynamic modulation of the non-canonical NF-κB signaling pathway for HIV shock and kill.

HIV cure still remains an elusive target. The "Shock and Kill" strategy which aims to reactivate HIV from latently infected cells and subsequently kill them through virally induced apoptosis or immune mediated clearance, is the subject of widespread investigation. NF-κB is a ubiquitous transcription factor which serves as a point of confluence for a number of intracellular signaling pathways and is also a crucial regulator of HIV transcription. Due to its relatively lower side effect profile and proven role in HIV transcription, the non-canonical NF-κB pathway has emerged as an attractive target for HIV reactivation, as a first step towards eradication. A comprehensive review examining this pathway in the setting of HIV and its potential utility to cure efforts is currently lacking. This review aims to summarize non-canonical NF-κB signaling and the importance of this pathway in HIV shock-and-kill efforts.

Risk of HBV reactivation in HCC patients undergoing combination therapy of PD-1 inhibitors and angiogenesis inhibitors in the antiviral era.

BACKGROUND: Although routine antiviral therapy has been implemented in HCC patients, the risk of HBV reactivation (HBVr) remains with the use of programmed cell death-1(PD-1) blockade-based combination immunotherapy and the relevant risk factors are also unclear. Therefore, we aimed to identify the incidence and risk factors of HBVr in HCC patients undergoing combination therapy of PD-1 inhibitors and angiogenesis inhibitors and concurrent first-line antivirals. METHODS: We included a total of 218 HBV-related HCC patients with first-line antivirals who received PD-1 inhibitors alone or together with angiogenesis inhibitors. According to the anti-tumor therapy modalities, patients were divided into PD-1 inhibitors monotherapy group (anti-PD-1 group) and combination therapy group (anti-PD-1 plus angiogenesis inhibitors group). The primary study endpoint was the incidence of HBVr. RESULTS: HBVr occurred in 16 (7.3%) of the 218 patients, 2 cases were found in the anti-PD-1 group and the remaining 14 cases were in the combination group. The Cox proportional hazard model identified 2 independent risk factors for HBVr: combination therapy (hazard ratio [HR], 4.608, 95%CI 1.010-21.016, P = 0.048) and hepatitis B e antigen (HBeAg) positive (HR, 3.695, 95%CI 1.246-10.957, P = 0.018). Based on the above results, we developed a simple risk-scoring system and found that the high-risk group (score = 2) developed HBVr more frequently than the low-risk group (score = 0) (Odds ratio [OR], 17.000, 95%CI 1.946-148.526, P = 0.01). The area under the ROC curve (AUC-ROC) was 7.06 (95%CI 0.581-0.831, P = 0.006). CONCLUSION: HBeAg-positive patients receiving combination therapy have a 17-fold higher risk of HBVr than HBeAg-negative patients with PD-1 inhibitors monotherapy.

Differential carbonic anhydrase activities control EBV-induced B-cell transformation and lytic cycle reactivation.

Epstein-Barr virus (EBV) contributes to ~1% of all human cancers including several B-cell neoplasms. A characteristic feature of EBV life cycle is its ability to transform metabolically quiescent B-lymphocytes into hyperproliferating B-cell blasts with the establishment of viral latency, while intermittent lytic cycle induction is necessary for the production of progeny virus. Our RNA-Seq analyses of both latently infected naïve B-lymphocytes and transformed B-lymphocytes upon lytic cycle replication indicate a contrasting expression pattern of a membrane-associated carbonic anhydrase isoform CA9, an essential component for maintaining cell acid-base homeostasis. We show that while CA9 expression is transcriptionally activated during latent infection model, lytic cycle replication restrains its expression. Pharmacological inhibition of CA-activity using specific inhibitors retards EBV induced B-cell transformation, inhibits B-cells outgrowth and colony formation ability of transformed B-lymphocytes through lowering the intracellular pH, induction of cell apoptosis and facilitating degradation of CA9 transcripts. Reanalyses of ChIP-Seq data along with utilization of EBNA2 knockout virus, ectopic expression of EBNA2 and sh-RNA mediated knockdown of CA9 expression we further demonstrate that EBNA2 mediated CA9 transcriptional activation is essential for EBV latently infected B-cell survival. In contrast, during lytic cycle reactivation CA9 expression is transcriptionally suppressed by the key EBV lytic cycle transactivator, BZLF1 through its transactivation domain. Overall, our study highlights the dynamic alterations of CA9 expression and its activity in regulating pH homeostasis act as one of the major drivers for EBV induced B-cell transformation and subsequent B-cell lymphomagenesis.

New latency-promoting agents for a block-and-lock functional cure strategy.

PURPOSE OF REVIEW: Currently, HIV-infected patients are treated with antiretroviral therapy. However, when the treatment is interrupted, viral rebound occurs from latently infected cells. Therefore, scientists aim to develop an HIV-1 cure which eradicates or permanently silences the latent reservoir. RECENT FINDINGS: Previously, scientists focused on the shock-and-kill cure strategy, which aims to eradicate the latent reservoir using latency-reactivating agents. Limited success shifts the interest towards the block-and-lock cure approach, which aims to achieve a functional cure by "blocking" HIV-1 transcription and "locking" the provirus in a deep latent state, resistant to treatment-interruption. In this strategy, latency promoting agents are used to induce transcriptional silencing and alter the epigenetics environment at the HIV promotor. SUMMARY: For the block-and-lock cure strategy to succeed more investigation into the transcriptional and epigenetic regulation of HIV-1 gene expression is necessary to design optimal latency-promoting agents. In this review, we will discuss the latency promoting agents that have been described in literature during the past 2 years (2022-2023).

Glucocorticoid receptor and specificity protein 1 (Sp1) or Sp3, but not the antibiotic Mithramycin A, stimulates human alphaherpesvirus 1 (HSV-1) replication.

Following acute human alphaherpesvirus 1 (HSV-1) infection of oral-facial mucosal surfaces, sensory neurons in trigeminal ganglia (TG) are important sites for life-long latency. Neurons in the central nervous system, including brainstem, also harbor viral genomes during latency. Periodically, certain cellular stressors trigger reactivation from latency, which can lead to recurrent HSV-1 disease: herpes labialis, herpes stromal keratitis, and encephalitis for example. Activation of the glucocorticoid receptor (GR) by stressful stimuli enhances HSV-1 gene expression, replication, and explant-induced reactivation. GR and certain stress-induced Krüppel like factors (KLF) cooperatively transactivate cis-regulatory modules (CRM) that drive expression of viral transcriptional regulatory proteins (ICP0, ICP4, and ICP27). These CRMs lack GR response elements (GRE); however, specificity protein 1 (Sp1) binding sites are crucial for GR and KLF15 or KLF4 mediated transactivation. Hence, we tested whether Sp1 or Sp3 regulate viral replication and transactivation of the ICP0 promoter. During early stages of explant-induced reactivation from latency, the number of Sp3+ TG neurons were significantly higher relative to TG from latently infected mice. Conversely, Sp1+ TG neurons were only increased in females, but not male mice, during explant-induced reactivation. Sp1 siRNA significantly reduced HSV-1 replication in cultured mouse (Neuro-2A) and monkey (CV-1) cells. Mithramycin A, an antibiotic that has anti-tumor activity preferentially interacts with GC-rich DNA, including Sp1 binding sites, significantly reduced HSV-1 replication indicating it has antiviral activity. GR and Sp1 or Sp3 transactivated the HSV-1 ICP0 promoter in Neuro-2A and CV-1 cells confirming these transcription factors enhance viral replication and gene expression.

CRISPRpi: Inducing and Curing Prophage Using the CRISPR Interference.

We present here a CRISPR-interference-based protocol to trigger prophage induction, even for non-inducible prophages. This method can also be used to cure the prophage from the bacterial host. The method is based on silencing of the phage's repressor transcription, thanks to CRISPR interference. Plasmid electroporation is used to bring the CRISPRi system into the bacteria, specifically on a plasmid carrying spacers targeting the prophage repressor. This method enables prophage induction and curation in a week or two with a high efficiency.

Simian varicella virus infection and reactivation in rhesus macaques trigger cytokine and Aß40/42 alterations in serum and cerebrospinal fluid.

Simian varicella virus (SVV) produces peripheral inflammatory responses during varicella (primary infection) and zoster (reactivation) in rhesus macaques (RM). However, it is unclear if peripheral measures are accurate proxies for central nervous system (CNS) responses. Thus, we analyzed cytokine and Aß42/Aß40 changes in paired serum and cerebrospinal fluid (CSF) during the course of infection. During varicella and zoster, every RM had variable changes in serum and CSF cytokine and Aß42/Aß40 levels compared to pre-inoculation levels. Overall, peripheral infection appears to affect CNS cytokine and Aß42/Aß40 levels independent of serum responses, suggesting that peripheral disease may contribute to CNS disease.

HIV Reservoirs and Treatment Strategies toward Curing HIV Infection.

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the "Shock and Kill", and "Block and Lock" strategies.

Reactivation of Epstein-Barr virus among intensive care patients: a prospective observational study.

PURPOSE: Herpesvirus reactivation has been documented among patients in the intensive care unit (ICU) and is associated with increased morbidity and mortality, particularly for cytomegalovirus (CMV). Epstein-Barr virus (EBV) has been poorly studied despite >95% of the population being seropositive. Our preliminary study suggested an association between EBV reactivation and increased morbidity and mortality. This study aimed to investigate this association among patients admitted to the ICU. METHODS: In this multicenter prospective study, polymerase chain reaction was performed to quantify EBV in patients upon ICU admission and then twice a week during their stay. Follow-up was 90 days. RESULTS: The study included 129 patients; 70 (54.3%) had EBV reactivation. On day 90, there was no difference in mortality rates between patients with and without reactivation (25.7% vs 15.3%, p = 0.22). Patients with EBV reactivation at admission had increased mortality compared with those without reactivation and those with later reactivation. EBV reactivation was associated with increased morbidity. Patients with EBV reactivation had fewer ventilator-free days at day 28 than those without reactivation (18 [1-22] vs. 21 days [5-26], p = 0.037) and a higher incidence of acute respiratory distress syndrome (34.3% vs. 17%, p = 0.04), infections (92.9% vs. 78%, p = 0.03), and septic shock (58.6% vs. 32.2%, p = 0.004). More patients with EBV reactivation required renal replacement therapy (30% vs. 11.9%, p = 0.02). EBV reactivation was also associated with a more inflammatory immune profile. CONCLUSION: While EBV reactivation was not associated with increased 90-day mortality, it was associated with significantly increased morbidity.

Consensus Guidelines: Best Practices for the Prevention, Detection and Management of Hepatitis B Virus Reactivation in Clinical Trials with Immunosuppressive/Immunomodulatory Therapy.

Hepatitis B virus reactivation (HBVr) during and after immunosuppressive/immunomodulatory (IS/IM) therapy is associated with significant morbidity and mortality, including hepatic decompensation and acute liver failure. The risk of HBVr with IS/IM has been heterogeneous and often unpredictable. As a result, patients with active or previous HBV infection are often excluded from clinical drug trials of such agents. Thorough screening for HBV infection, antiviral prophylaxis, and careful monitoring for HBVr have proven to be effective in reducing the rate of HBVr and improving its outcome in the context of IS/IM. Therefore, safe enrollment and management of certain HBV-marker-positive patients in clinical trials is possible. There is a great, unmet need for consistent, evidence-based recommendations for best practices pertaining to enrollment, monitoring, and management of HBVr in clinical trial participants receiving IS/IM. The aim of these consensus guidelines is to provide a step-by-step blueprint to safely enroll, monitor and manage the patient with inactive chronic or resolved HBV in IS/IM clinical trials from the time of screening through to the end of post-treatment follow up.

Effects of human herpesvirus 6B reactivation on cognitive function in cord blood transplant recipients: a prospective multicenter study.

This prospective multicenter study aimed to determine the effects of human herpesvirus-6B (HHV-6B) reactivation on central nervous system (CNS) function in cord blood transplant (CBT) recipients. Our focus was to track HHV-6B reactivation and evaluate its association with delirium and cognitive function, specifically in the domains of verbal memory, attention/processing speed, and quality of life (QOL). A cohort of 38 patients participated in this study. Of the 37 patients evaluated, seven (18.9%) developed delirium, with six of these cases emerging after HHV-6B reactivation (median lag, 7 days). Evaluation of verbal memory showed that the final trial score for unrelated words at 70 days after transplantation was significantly lower than that before preconditioning (P = 0.004) among patients (n = 15) who experienced higher-level HHV-6B reactivation (median or higher maximum plasma HHV-6 DNA load for participating patients). Patients without higher-level reactivation did not show significant declines in verbal memory scores. QOL was assessed using the 36-item Short-Form Health Survey, and the social functioning score 1 year post-transplantation was significantly lower in patients who experienced higher-level HHV-6B reactivation than in those who did not. Our findings suggest that higher-level HHV-6B reactivation can detrimentally affect certain cognitive functions in CBT recipients.

Absence of CD80 reduces HSV-1 replication in the eye and delays reactivation but not latency levels.

Herpes simplex virus-1 (HSV-1) infections are among the most frequent serious viral eye infections in the U.S. and are a major cause of viral-induced blindness. HSV-1 infection is known to induce T cell activation, proliferation, and differentiation that play crucial roles in the development of virus-induced inflammatory lesions, leading to eye disease and causing chronic corneal damage. CD80 is a co-stimulatory molecule and plays a leading role in T cell differentiation. Previous efforts to limit lesion severity by controlling inflammation at the cellular level led us to ask whether mice knocked out for CD80 would show attenuated virus replication following reactivation. By evaluating the effects of CD80 activity on primary and latent infection, we found that in the absence of CD80, virus replication in the eyes and virus reactivation in latent trigeminal ganglia were both significantly reduced. However, latency in latently infected CD80-/- mice did not differ significantly from that in wild-type (WT) control mice. Reduced virus replication in the eyes of CD80-/- mice correlated with significantly expanded CD11c gene expression as compared to WT mice. Taken together, our results indicate that suppression of CD80 could offer significant beneficial therapeutic effects in the treatment of Herpes Stromal Keratitis (HSK).IMPORTANCEOf the many problems associated with recurrent ocular infection, reducing virus reactivation should be a major goal of controlling ocular herpes simplex virus-1 (HSV-1) infection. In this study, we have shown that the absence of CD80 reduces HSV-1 reactivation, which marks the establishment of a previously undescribed mechanism underlying viral immune evasion that could be exploited to better manage HSV infection.

Prevention of hepatitis B reactivation in patients with hematologic malignancies treated with novel systemic therapies: Who and Why?

The risk of reactivation in patients with chronic or past/resolved hepatitis B virus (HBV) infection receiving chemotherapy or immunosuppressive drugs is a well-known possibility. The indication of antiviral prophylaxis with nucleo(t)side analogue is given according to the risk of HBV reactivation of the prescribed therapy. Though the advent of new drugs is occurring in all the field of medicine, in the setting of hematologic malignancies the last few years have been characterized by several drug classes and innovative cellular treatment. As novel therapies, there are few data about the rate of HBV reactivation and the decision of starting or not an antiviral prophylaxis could be challenging. Moreover, patients are often treated with a combination of different drugs, so evaluating the actual role of these new therapies in increasing the risk of HBV reactivation is difficult. First results are now available, but further studies are still needed. Patients with chronic HBV infection [hepatitis B surface antigen (HBsAg) positive] are reasonably all treated. Past/resolved HBV patients (HBsAg negative) are the actual area of uncertainty where it could be difficult choosing between prophylaxis and pre-emptive strategy.