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4.
PLoS Pathog ; 15(8): e1007991, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425551

RESUMO

Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Ativação Viral/imunologia , Latência Viral/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Depsipeptídeos/farmacologia , Diterpenos/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Carga Viral , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
5.
World J Gastroenterol ; 25(26): 3299-3312, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31341357

RESUMO

Reactivation of hepatitis B virus (HBV) replication is characterized by increased HBV-DNA serum values of about 1 log or by HBV DNA turning positive if previously undetectable in serum, possibly associated with liver damage and seldom life-threatening. Due to HBV reactivation, hepatitis B surface antigen (HBsAg)-negative/anti-HBc-positive subjects may revert to HBsAg-positive. In patients with hemo-lymphoproliferative disease, the frequency of HBV reactivation depends on the type of lymphoproliferative disorder, the individual's HBV serological status and the potency and duration of immunosuppression. In particular, it occurs in 10%-50% of the HBsAg-positive and in 2%-25% of the HBsAg- negative/anti-HBc-positive, the highest incidences being registered in patients receiving rituximab-based therapy. HBV reactivation can be prevented by accurate screening of patients at risk and by a pharmacological prophylaxis with anti-HBV nucleo(t)sides starting 2-3 wk before the beginning of immunosuppressive treatment and covering the entire period of administration of immunosuppressive drugs and a long subsequent period, the duration of which depends substantially on the degree of immunodepression achieved. Patients with significant HBV replication before immunosuppressive therapy should receive anti-HBV nucleo(t)sides as a long-term (may be life-long) treatment. This review article is mainly directed to doctors engaged every day in the treatment of patients with onco-lymphoproliferative diseases, so that they can broaden their knowledge on HBV infection and on its reactivation induced by the drugs with high immunosuppressive potential that they use in the care of their patients.


Assuntos
Antibioticoprofilaxia/métodos , Antivirais/uso terapêutico , Vírus da Hepatite B/isolamento & purificação , Hepatite B/prevenção & controle , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/tratamento farmacológico , DNA Viral/sangue , Hepatite B/imunologia , Hepatite B/virologia , Anticorpos Anti-Hepatite B/sangue , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Transtornos Linfoproliferativos/imunologia , Fatores de Tempo , Ativação Viral/efeitos dos fármacos , Ativação Viral/imunologia
6.
PLoS Pathog ; 15(5): e1007669, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31042779

RESUMO

HIV-1 is dependent on the host cell for providing the metabolic resources for completion of its viral replication cycle. Thus, HIV-1 replicates efficiently only in activated CD4+ T cells. Barriers preventing HIV-1 replication in resting CD4+ T cells include a block that limits reverse transcription and also the lack of activity of several inducible transcription factors, such as NF-κB and NFAT. Because FOXO1 is a master regulator of T cell functions, we studied the effect of its inhibition on T cell/HIV-1 interactions. By using AS1842856, a FOXO1 pharmacologic inhibitor, we observe that FOXO1 inhibition induces a metabolic activation of T cells with a G0/G1 transition in the absence of any stimulatory signal. One parallel outcome of this change is the inhibition of the activity of the HIV restriction factor SAMHD1 and the activation of the NFAT pathway. FOXO1 inhibition by AS1842856 makes resting T cells permissive to HIV-1 infection. In addition, we found that FOXO1 inhibition by either AS1842856 treatment or upon FOXO1 knockdown induces the reactivation of HIV-1 latent proviruses in T cells. We conclude that FOXO1 has a central role in the HIV-1/T cell interaction and that inhibiting FOXO1 with drugs such as AS1842856 may be a new therapeutic shock-and-kill strategy to eliminate the HIV-1 reservoir in human T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteína Forkhead Box O1/antagonistas & inibidores , Regulação da Expressão Gênica , Infecções por HIV/virologia , HIV-1/imunologia , Ativação Viral/imunologia , Replicação Viral , Animais , Linfócitos T CD4-Positivos/virologia , Ciclo Celular , Proteína Forkhead Box O1/genética , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Células Jurkat , Ativação Linfocitária/imunologia , Macaca fascicularis , Masculino , Latência Viral
8.
Ann Hematol ; 98(8): 1877-1883, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144019

RESUMO

Secondary poor graft function (sPGF) is defined as secondary cytopenia after initial engraftment of allogeneic stem cell transplantation (allo-SCT). It has been shown to be associated with poor prognosis; however, there are very few reports on the incidence, risk factors, and outcomes of sPGF. Between January 2015 and December 2015, 564 patients, who received transplantation at Peking University People's Hospital, were retrospectively reviewed. Among the 490 patients who achieved initial engraftment of both neutrophils and platelets, 28 patients developed sPGF. The cumulative incidence of sPGF on day 100 was 5.7%. The median time of sPGF was 54.5 (34-91) days after transplantation. Low (< median) CD34+ cell dose (p = 0.019, HR 3.07 (95% CI, 1.207-7.813)), Epstein-Barr Virus (EBV) reactivation (p = 0.009, HR 3.648 (95%CI, 1.382-9.629)), and cytomegalovirus (CMV) reactivation (p = 0.003, HR 7.827 (95%CI, 2.002-30.602)) were identified as independent risk factors for sPGF. There was no significant difference in PGF incidence between the matched sibling donor (MSD) group and haploidentical donor (HID) group (p = 0.44). The overall survival of patients with sPGF at 1 year after transplantation was significantly poorer than that of patients with good graft function (GGF) (50.5% versus 87.2%, p < 0.001). In conclusion, sPGF developed in 5.7% patients after allo-SCT, especially in patients with CMV, EBV reactivation, or infusion with a low dose of CD34+ cells. The prognosis of sPGF is still poor owing to a lack of standard treatment.


Assuntos
Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/virologia , Doença Enxerto-Hospedeiro/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Ativação Viral/imunologia , Adolescente , Adulto , Idoso , Antígenos CD34/imunologia , Criança , Pré-Escolar , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/patologia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Feminino , Sobrevivência de Enxerto/fisiologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/virologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Humanos , Leucemia/mortalidade , Leucemia/patologia , Leucemia/virologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/virologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Haploidêntico
9.
PLoS Pathog ; 15(5): e1007802, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31116788

RESUMO

A major barrier to curing HIV-1 is the long-lived latent reservoir that supports re-emergence of HIV-1 upon treatment interruption. Targeting this reservoir will require mechanistic insights into the establishment and maintenance of HIV-1 latency. Whether T cell signaling at the time of HIV-1 infection influences productive replication or latency is not fully understood. We used a panel of chimeric antigen receptors (CARs) with different ligand binding affinities to induce a range of signaling strengths to model differential T cell receptor signaling at the time of HIV-1 infection. Stimulation of T cell lines or primary CD4+ T cells expressing chimeric antigen receptors supported HIV-1 infection regardless of affinity for ligand; however, only signaling by the highest affinity receptor facilitated HIV-1 expression. Activation of chimeric antigen receptors that had intermediate and low binding affinities did not support provirus transcription, suggesting that a minimal signal is required for optimal HIV-1 expression. In addition, strong signaling at the time of infection produced a latent population that was readily inducible, whereas latent cells generated in response to weaker signals were not easily reversed. Chromatin immunoprecipitation showed HIV-1 transcription was limited by transcriptional elongation and that robust signaling decreased the presence of negative elongation factor, a pausing factor, by more than 80%. These studies demonstrate that T cell signaling influences HIV-1 infection and the establishment of different subsets of latently infected cells, which may have implications for targeting the HIV-1 reservoir.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Provírus/imunologia , Latência Viral/imunologia , Humanos , Células Jurkat , Transdução de Sinais , Ativação Viral/imunologia , Replicação Viral/imunologia
10.
J Clin Neurosci ; 64: 18-21, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30948314

RESUMO

Survival outcomes for patients with glioblastoma (GBM) are universally poor with only a small percentage of patients surviving five years beyond initial diagnosis. Activation of the immune system against tumor cells is the basis of immunotherapy and aims to facilitate long-term immune surveillance and tumor suppression. Cytomegalovirus (CMV) has emerged as an immunologic target in GBM given that tumor cells have been shown to express the CMV-associated proteins IE1 and pp65. Moreover, vaccine therapy targeting CMV antigens has promoted improved survival outcomes with long-term survivors. In this report, we present the case of a 69 year-old woman with GBM who survived seven years post-diagnosis. Following tumor resection, the patient underwent concomitant radiation and temozolomide therapy that was complicated by CMV colitis and abdominal abscesses. Despite not receiving adjuvant temozolomide, the patient demonstrated a five year progression-free survival before requiring re-resection for radiation necrosis. Following re-resection, the patient survived for two additional years. As the patient's tumor stained positive for CMV antigens IE1 and pp65, it is hypothesized that she developed an immune response against CMV during recovery that contributed to anti-tumor surveillance and prolonged survival. Overall, this case supports further investigation into the role of CMV and immunotherapy in GBM.


Assuntos
Neoplasias Encefálicas/imunologia , Colite/virologia , Infecções por Citomegalovirus/imunologia , Glioblastoma/imunologia , Hospedeiro Imunocomprometido , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/virologia , Quimiorradioterapia/métodos , Colite/complicações , Feminino , Glioblastoma/patologia , Glioblastoma/virologia , Humanos , Proteínas Imediatamente Precoces/imunologia , Fosfoproteínas/imunologia , Temozolomida/uso terapêutico , Proteínas da Matriz Viral/imunologia , Ativação Viral/imunologia
11.
BMJ Case Rep ; 12(3)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30936341

RESUMO

The use of immunosuppressing agents can act as a catalyst for viral reactivation, promoting systemic infection with organ involvement. Current literature remains sparse on this topic but does provide individual case reports involving single viruses. We present the case of an immunocompromised patient with skin lesions, pancreatitis, colitis and hepatitis. Work-up revealed varicella zoster virus, which likely put the patient at risk for multi-organ involvement, as well as clinical suspicion of other implicated viruses, specifically herpes simplex virus and cytomegalovirus. A high clinical index of suspicion along with biopsy guidance for viral involvement in immunocompromised patients is crucial for early diagnosis and treatment of these conditions.


Assuntos
Antivirais/uso terapêutico , Colite/virologia , Hepatite/virologia , Doenças da Boca/virologia , Pancreatite/virologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Dermatopatias Virais/patologia , Ativação Viral/imunologia , Infecções por Citomegalovirus/imunologia , Evolução Fatal , Feminino , Herpes Simples/imunologia , Herpes Zoster/imunologia , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , Mucosa Bucal/virologia , Multimorbidade , Conforto do Paciente , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Simplexvirus/imunologia , Dermatopatias Virais/terapia , Latência Viral
12.
PLoS Pathog ; 15(3): e1007595, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30845208

RESUMO

Despite a broad cell-type tropism, cytomegalovirus (CMV) is an evidentially pulmonary pathogen. Predilection for the lungs is of medical relevance in immunocompromised recipients of hematopoietic cell transplantation, in whom interstitial CMV pneumonia is a frequent and, if left untreated, fatal clinical manifestation of human CMV infection. A conceivable contribution of CMV to airway diseases of other etiology is an issue that so far attracted little medical attention. As the route of primary CMV infection upon host-to-host transmission in early childhood involves airway mucosa, coincidence of CMV airway infection and exposure to airborne environmental antigens is almost unavoidable. For investigating possible consequences of such a coincidence, we established a mouse model of airway co-exposure to CMV and ovalbumin (OVA) representing a protein antigen of an inherently low allergenic potential. Accordingly, intratracheal OVA exposure alone failed to sensitize for allergic airway disease (AAD) upon OVA aerosol challenge. In contrast, airway infection at the time of OVA sensitization predisposed for AAD that was characterized by airway inflammation, IgE secretion, thickening of airway epithelia, and goblet cell hyperplasia. This AAD histopathology was associated with a T helper type 2 (Th2) transcription profile in the lungs, including IL-4, IL-5, IL-9, and IL-25, known inducers of Th2-driven AAD. These symptoms were all prevented by a pre-challenge depletion of CD4+ T cells, but not of CD8+ T cells. As to the underlying mechanism, murine CMV activated migratory CD11b+ as well as CD103+ conventional dendritic cells (cDCs), which have been associated with Th2 cytokine-driven AAD and with antigen cross-presentation, respectively. This resulted in an enhanced OVA uptake and recruitment of the OVA-laden cDCs selectively to the draining tracheal lymph nodes for antigen presentation. We thus propose that CMV, through activation of migratory cDCs in the airway mucosa, can enhance the allergenic potential of otherwise poorly allergenic environmental protein antigens.


Assuntos
Alérgenos/metabolismo , Citomegalovirus/metabolismo , Células Dendríticas/imunologia , Alérgenos/efeitos adversos , Animais , Apresentação do Antígeno/imunologia , Antígenos CD11/imunologia , Citomegalovirus/patogenicidade , Células Dendríticas/microbiologia , Modelos Animais de Doenças , Feminino , Hipersensibilidade , Inflamação , Pulmão/fisiopatologia , Pulmão/virologia , Pneumopatias/etiologia , Pneumopatias/virologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina , Células Th2 , Ativação Viral/imunologia
13.
Clin Immunol ; 200: 19-23, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639657

RESUMO

Conflicting results have been reported regarding human herpes virus (HHV) reactivation in patients with rheumatoid arthritis (RA). To explore this link, 74 RA patients were selected and compared to 42 first degree relatives (FDR) from probands with RA and 25 healthy controls from the Tatarstan women cohort. The serological analysis was done by testing anti-HSV/CMV/EBV IgM, IgG, plus the IgG avidity index, and completed by evaluating HSV/CMV/EBV DNA by PCR. Results from these analyses reveal: (i) a long lasting infection of HHV in RA, FDR and healthy controls (IgG seroconversion >97%); (ii) an elevated IgM anti-HHV response in seroconverted RA patients which is related to HSV1/2 reactivation (HSV1/2 PCR+); and (iii) a multi-reactive IgM HHV burden profile associated with disease activity (DAS28). In conclusion, HSV1/2 reactivation in seroconverted RA patients is associated with an abnormal anti-HHV immune response, which was reflected in IgM HHV burden, and in activity disease profile.


Assuntos
Anticorpos Antivirais/imunologia , Artrite Reumatoide/imunologia , Herpesviridae/imunologia , Imunoglobulina M/imunologia , Ativação Viral/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/virologia , Estudos de Casos e Controles , Citomegalovirus/genética , Citomegalovirus/imunologia , DNA Viral/análise , Família , Feminino , Herpesviridae/genética , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Soroconversão , Índice de Gravidade de Doença
14.
J Virol ; 93(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602604

RESUMO

Gammaherpesviruses are ubiquitous viruses that establish lifelong infections. Importantly, these viruses are associated with numerous cancers and lymphoproliferative diseases. While risk factors for developing gammaherpesvirus-driven cancers are poorly understood, it is clear that elevated viral reactivation from latency often precedes oncogenesis. Here, we demonstrate that the liver X receptor alpha isoform (LXRα) restricts gammaherpesvirus reactivation in an anatomic-site-specific manner. We have previously demonstrated that deficiency of both LXR isoforms (α and ß) leads to an increase in fatty acid and cholesterol synthesis in primary macrophage cultures, with a corresponding increase in gammaherpesvirus replication. Interestingly, expression of fatty acid synthesis genes was not derepressed in LXRα-deficient hosts, indicating that the antiviral effects of LXRα are independent of lipogenesis. Additionally, the critical host defenses against gammaherpesvirus reactivation, virus-specific CD8+ T cells and interferon (IFN) signaling, remained intact in the absence of LXRα. Remarkably, using a murine gammaherpesvirus 68 (MHV68) reporter virus, we discovered that LXRα expression dictates the cellular tropism of MHV68 in the peritoneal cavity. Specifically, LXRα-/- mice exhibit reduced latency within the peritoneal B cell compartment and elevated latency within F4/80+ cells. Thus, LXRα restricts gammaherpesvirus reactivation through a novel mechanism that is independent of the known CD8+ T cell-based antiviral responses or changes in lipid synthesis and likely involves changes in the tropism of MHV68 in the peritoneal cavity.IMPORTANCE Liver X receptors (LXRs) are nuclear receptors that mediate cholesterol and fatty acid homeostasis. Importantly, as ligand-activated transcription factors, LXRs represent potential targets for the treatment of hypercholesterolemia and atherosclerosis. Here, we demonstrate that LXRα, one of the two LXR isoforms, restricts reactivation of latent gammaherpesvirus from peritoneal cells. As gammaherpesviruses are ubiquitous oncogenic agents, LXRs may represent a targetable host factor for the treatment of poorly controlled gammaherpesvirus infection and associated lymphomagenesis.


Assuntos
Linfócitos B/virologia , Gammaherpesvirinae/imunologia , Gammaherpesvirinae/fisiologia , Infecções por Herpesviridae/imunologia , Receptores X do Fígado/imunologia , Cavidade Peritoneal/virologia , Latência Viral/imunologia , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Feminino , Infecções por Herpesviridae/virologia , Interações Hospedeiro-Patógeno/imunologia , Interferons/imunologia , Lipogênese/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/imunologia , Peritônio/virologia , Transdução de Sinais/imunologia , Tropismo/imunologia , Ativação Viral/imunologia , Replicação Viral/imunologia
15.
J Clin Invest ; 129(2): 875-886, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30511963

RESUMO

BACKGROUND: Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5-vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA. METHODS: Healthy VZV-seropositive Kenyan women (n = 44) were immunized with high-dose live attenuated VZV vaccine, and we assessed the expression on CD4+ T cells isolated from blood, cervix, and rectum of IA markers including CD38 and HLA-DR and of markers of cell migration and tissue retention, as well as the concentration of genital and intestinal cytokines. A delayed-start group (n = 22) was used to control for natural variations in these parameters. RESULTS: Although immunogenic, VZV vaccination did not result in significant difference in the frequency of cervical activated (HLA-DR+CD38+) CD4+ T cells (median 1.61%, IQR 0.93%-2.76%) at 12 weeks after vaccination when compared with baseline (median 1.58%, IQR 0.75%-3.04%), the primary outcome for this study. VZV vaccination also had no measurable effect on any of the IA parameters at 4, 8, and 12 weeks after vaccination. CONCLUSION: This study provides the first evidence to our knowledge about the effects of VZV vaccination on human mucosal IA status and supports further evaluation of VZV as a potential vector for an HIV vaccine. TRIAL REGISTRATION: ClinicalTrials.gov NCT02514018. FUNDING: Primary support from the Canadian Institutes for Health Research (CIHR). For other sources, see Acknowledgments.


Assuntos
Vacinas contra a AIDS , Linfócitos T CD4-Positivos/imunologia , HIV-1/fisiologia , Herpesvirus Humano 3 , Ativação Viral , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/imunologia , Adulto , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Feminino , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/imunologia , Humanos , Quênia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Infecção pelo Vírus da Varicela-Zoster/patologia , Infecção pelo Vírus da Varicela-Zoster/prevenção & controle , Ativação Viral/efeitos dos fármacos , Ativação Viral/imunologia
16.
Hum Vaccin Immunother ; 15(1): 45-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30130445

RESUMO

Among the inflammatory rheumatic diseases, SLE is associated with the highest risk of herpes zoster reactivation relative to age. The reported incidence of herpes zoster infection in SLE ranges from 6.4 to 91.4/1000 patient-years, with main risk factors being major organ disease, immunosuppressive and biological therapies. Although herpes zoster in SLE is manageable with anti-viral treatment, complications such as superimposed bacterial infection, post-herpetic neuralgia may ensue. The low rate of herpes zoster vaccination in SLE is related to the lack of awareness, fear of the risk of vaccine-induced infection and disease flare, cost, as well as the lack of explicit recommendations of vaccine use for the paucity of data in immunocompromised and younger subjects. The recent availability of the non-live subunit and inactivated herpes zoster vaccines has provided more opportunities for SLE patients to be protected against this viral infection. More clinical trials are clearly needed in SLE to confirm safety, immunogenicity and efficacy of the herpes zoster vaccines.


Assuntos
Vacina contra Herpes Zoster/administração & dosagem , Hospedeiro Imunocomprometido , Lúpus Eritematoso Sistêmico/complicações , Neuralgia Pós-Herpética/prevenção & controle , Vacinação , Humanos , Incidência , Lúpus Eritematoso Sistêmico/imunologia , Fatores de Risco , Potência de Vacina , Vacinas de Produtos Inativados/administração & dosagem , Ativação Viral/imunologia
17.
J Virol ; 93(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30404798

RESUMO

Rhesus macaques intrabronchially inoculated with simian varicella virus (SVV), the counterpart of human varicella-zoster virus (VZV), developed primary infection with viremia and rash, which resolved upon clearance of viremia, followed by the establishment of latency. To assess the role of CD4 T cell immunity in reactivation, monkeys were treated with a single 50-mg/kg dose of a humanized monoclonal anti-CD4 antibody; within 1 week, circulating CD4 T cells were reduced from 40 to 60% to 5 to 30% of the total T cell population and remained low for 2 months. Very low viremia was seen only in some of the treated monkeys. Zoster rash developed after 7 days in the monkey with the most extensive CD4 T cell depletion (5%) and in all other monkeys at 10 to 49 days posttreatment, with recurrent zoster in one treated monkey. SVV DNA was detected in the lung from two of five monkeys, in bronchial lymph nodes from one of the five monkeys, and in ganglia from at least two dermatomes in three of five monkeys. Immunofluorescence analysis of skin rash, lungs, lymph nodes, and ganglia revealed SVV ORF63 protein at the following sites: sweat glands in skin; type II cells in lung alveoli, macrophages, and dendritic cells in lymph nodes; and the neuronal cytoplasm of ganglia. Detection of SVV antigen in multiple tissues upon CD4 T cell depletion and virus reactivation suggests a critical role for CD4 T cell immunity in controlling varicella virus latency.IMPORTANCE Reactivation of latent VZV in humans can result in serious neurological complications. VZV-specific cell-mediated immunity is critical for the maintenance of latency. Similar to VZV in humans, SVV causes varicella in monkeys, establishes latency in ganglia, and reactivates to produce shingles. Here, we show that depletion of CD4 T cells in rhesus macaques results in SVV reactivation, with virus antigens found in zoster rash and SVV DNA and antigens found in lungs, lymph nodes, and ganglia. These results suggest the critical role of CD4 T cell immunity in controlling varicella virus latency.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Herpesviridae/imunologia , Depleção Linfocítica , Pele/imunologia , Varicellovirus/isolamento & purificação , Ativação Viral/imunologia , Latência Viral/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Modelos Animais de Doenças , Feminino , Gânglios/citologia , Gânglios/imunologia , Gânglios/virologia , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/virologia , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/virologia , Macaca mulatta , Masculino , Pele/citologia , Pele/virologia
19.
Ann Pharmacother ; 53(3): 294-310, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30203666

RESUMO

OBJECTIVE: To describe and quantify the incidence and morbidity of hepatitis B reactivation (HBVr) secondary to pharmaceutical agents (eg, rituximab, tumor necrosis factor inhibitors, direct-acting antivirals [DAAs] for hepatitis C) among patients with previously resolved hepatitis B infection. DATA SOURCES: The MEDLINE database was searched from inception through July 2018 using the terms hepatitis B + ( reactivation OR [drug or drug class linked to HBVr]). STUDY SELECTION AND DATA EXTRACTION: Relevant English-language cohort studies or randomized trials quantifying the incidence of HBVr secondary to pharmacotherapy among patients negative for hepatitis B surface antigen and DNA and positive for hepatitis B core antibody were included. DATA SYNTHESIS: Among 2045 articles, 102 met inclusion criteria. Receipt of rituximab was associated with the highest risk of HBVr (for oncological indication: 6.2% rate [225/3601 patients]) and subsequent hepatitis (up to 52.4% of all HBVr cases). Biologic agents for autoimmune disease were uncommonly associated with HBVr (2.4%, 56/2338), with only 4 cases of hepatitis, all attributable to rituximab. Reactivation caused by DAAs was rare (0.3%, 28/8398), with no cases of hepatitis. Relevance to Patient Care/Clinical Practice: This review compares and contrasts the incidence and clinical relevance of HBVr for various pharmacotherapies among patients with functionally cured hepatitis B, with discussion of appropriate risk mitigation strategies. CONCLUSIONS: Among patients with prior functional cure of hepatitis B, prophylactic antiviral therapy is recommended with rituximab administration irrespective of indication because of a high risk for HBVr-associated morbidity. Enhanced monitoring alone is reasonable for patients receiving nonrituximab biologics or DAAs.


Assuntos
Antivirais/uso terapêutico , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/virologia , Ativação Viral/efeitos dos fármacos , Antivirais/efeitos adversos , Estudos de Coortes , Feminino , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Viral/imunologia
20.
J Microbiol Immunol Infect ; 52(1): 1-8, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29158080

RESUMO

It is estimated that more than two billion people around the world have been infected by Hepatitis B virus (HBV). Reactivation of HBV (rHBV) is a potentially fatal complication after biological therapy. With the increasing use of biologics and targeted therapy in rheumatoid arthritis (RA) patients who are refractory to conventional synthetic disease-modifying anti-rheumatic drugs, rHBV in those with past infection has become increasingly problematic, especially in HBV-endemic regions. Among those receiving biological therapy, the risk of rHBV varies according to the status of HBV infection and the degree of biologic-related immunosuppression. As rHBV is largely preventable, it is imperative that the risk status of rHBV in RA patients receiving biological and targeted therapy be stratified. Therefore, the aim of this review was to summarize the reported data on rHBV, and propose management strategies for RA patients with different risks of rHBV based on evidence presented in the current literature.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Hepatite B/imunologia , Ativação Viral/imunologia , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Artrite Reumatoide/imunologia , Hepatite B/sangue , Hepatite B/etiologia , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Humanos , Terapia de Alvo Molecular
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