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Hepatitis C virus (HCV) infection resolves spontaneously in ∼25% of acutely infected humans where viral clearance is mediated primarily by virus-specific CD8+ T cells. Previous cross-sectional analysis of the CD8+ TCR repertoire targeting two immunodominant HCV epitopes reported widespread use of public TCRs shared by different subjects, irrespective of infection outcome. However, little is known about the evolution of the public TCR repertoire during acute HCV and whether cross-reactivity to other Ags can influence infectious outcome. In this article, we analyzed the CD8+ TCR repertoire specific to the immunodominant and cross-reactive HLA-A2–restricted nonstructural 3-1073 epitope during acute HCV in humans progressing to either spontaneous resolution or chronic infection and at ∼1 y after viral clearance. TCR repertoire diversity was comparable among all groups with preferential usage of the TCR-β V04 and V06 gene families. We identified a set of 13 public clonotypes in HCV-infected humans independent of infection outcome. Six public clonotypes used the V04 gene family. Several public clonotypes were long-lived in resolvers and expanded on reinfection. By mining publicly available data, we identified several low-frequency CDR3 sequences in the HCV-specific repertoire matching human TCRs specific for other HLA-A2–restricted epitopes from melanoma, CMV, influenza A, EBV, and yellow fever viruses, but they were of low frequency and limited cross-reactivity. In conclusion, we identified 13 new public human CD8+ TCR clonotypes unique to HCV that expanded during acute infection and reinfection. The low frequency of cross-reactive TCRs suggests that they are not major determinants of infectious outcome. Key Points Thirteen unique public clonotypes specific for the HCV NS3-1073 epitope are identified. Public clonotypes expanded during acute HCV infection and reinfection. Low frequency of cross-reactive TCRs targeting other HLA-A2–restricted epitopes is evident.
Sabrina Mazouz; Maude Boisvert; Mohamed S. Abdel-Hakeem; Omar Khedr; Julie Bruneau; Naglaa H. Shoukry. Expansion of Unique Hepatitis C Virus–Specific Public CD8+ T Cell Clonotypes during Acute Infection and Reinfection. The Journal of Immunology 2021, 207, 1180 -1193.
AMA StyleSabrina Mazouz, Maude Boisvert, Mohamed S. Abdel-Hakeem, Omar Khedr, Julie Bruneau, Naglaa H. Shoukry. Expansion of Unique Hepatitis C Virus–Specific Public CD8+ T Cell Clonotypes during Acute Infection and Reinfection. The Journal of Immunology. 2021; 207 (4):1180-1193.
Chicago/Turabian StyleSabrina Mazouz; Maude Boisvert; Mohamed S. Abdel-Hakeem; Omar Khedr; Julie Bruneau; Naglaa H. Shoukry. 2021. "Expansion of Unique Hepatitis C Virus–Specific Public CD8+ T Cell Clonotypes during Acute Infection and Reinfection." The Journal of Immunology 207, no. 4: 1180-1193.
The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8+ T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1+ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8+ T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62Lhi TCF-1+ subset and subsequent CD8+ T cell memory. Although central memory phenotype CD8+ T cells were formed in the absence of these cells, subsequent memory CD8+ T cell recall responses were compromised. Together, these results identify an important link between genome integrity maintenance and CD8+ T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8+ T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8+ T cell precursor pool may help reconcile models of the developmental origin of long-term CD8+ T cell memory.
Jonathan B. Johnnidis; Yuki Muroyama; Shin Foong Ngiow; Zeyu Chen; Sasikanth Manne; Zhangying Cai; Shufei Song; Jesse M. Platt; Jason M. Schenkel; Mohamed Abdel-Hakeem; Jean-Christophe Beltra; Allison R. Greenplate; Mohammed-Alkhatim A. Ali; Kito Nzingha; Josephine R. Giles; Christelle Harly; John Attanasio; Kristen E. Pauken; Bertram Bengsch; Michael A. Paley; Vesselin T. Tomov; Makoto Kurachi; Dario A. A. Vignali; Arlene H. Sharpe; Steven L. Reiner; Avinash Bhandoola; F. Bradley Johnson; E. John Wherry. Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage. Science Immunology 2021, 6, eabe3702 .
AMA StyleJonathan B. Johnnidis, Yuki Muroyama, Shin Foong Ngiow, Zeyu Chen, Sasikanth Manne, Zhangying Cai, Shufei Song, Jesse M. Platt, Jason M. Schenkel, Mohamed Abdel-Hakeem, Jean-Christophe Beltra, Allison R. Greenplate, Mohammed-Alkhatim A. Ali, Kito Nzingha, Josephine R. Giles, Christelle Harly, John Attanasio, Kristen E. Pauken, Bertram Bengsch, Michael A. Paley, Vesselin T. Tomov, Makoto Kurachi, Dario A. A. Vignali, Arlene H. Sharpe, Steven L. Reiner, Avinash Bhandoola, F. Bradley Johnson, E. John Wherry. Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage. Science Immunology. 2021; 6 (55):eabe3702.
Chicago/Turabian StyleJonathan B. Johnnidis; Yuki Muroyama; Shin Foong Ngiow; Zeyu Chen; Sasikanth Manne; Zhangying Cai; Shufei Song; Jesse M. Platt; Jason M. Schenkel; Mohamed Abdel-Hakeem; Jean-Christophe Beltra; Allison R. Greenplate; Mohammed-Alkhatim A. Ali; Kito Nzingha; Josephine R. Giles; Christelle Harly; John Attanasio; Kristen E. Pauken; Bertram Bengsch; Michael A. Paley; Vesselin T. Tomov; Makoto Kurachi; Dario A. A. Vignali; Arlene H. Sharpe; Steven L. Reiner; Avinash Bhandoola; F. Bradley Johnson; E. John Wherry. 2021. "Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage." Science Immunology 6, no. 55: eabe3702.
The transcriptional programs that regulate CD8 T-cell differentiation and function in the context of viral infections or tumor immune surveillance have been extensively studied; yet how long noncoding RNAs (lncRNAs) and the loci that transcribe them contribute to the regulation of CD8 T cells during viral infections remains largely unexplored. Here, we report that transcription of the lncRNAMorrbidis specifically induced by T-cell receptor (TCR) and type I IFN stimulation during the early stages of acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. In response to type I IFN, theMorrbidRNA and its locus control CD8 T cell expansion, survival, and effector function by regulating the expression of the proapoptotic factor,Bcl2l11, and by modulating the strength of the PI3K–AKT signaling pathway. Thus, our results demonstrate that inflammatory cue-responsive lncRNA loci represent fundamental mechanisms by which CD8 T cells are regulated in response to pathogens and potentially cancer.
Jonathan J. Kotzin; Fany Iseka; Jasmine Wright; Megha G. Basavappa; Megan L. Clark; Mohammed-Alkhatim Ali; Mohamed S. Abdel-Hakeem; Tanner F. Robertson; Walter Mowel; Leonel Joannas; Vanessa D. Neal; Sean Spencer; Camille M. Syrett; Montserrat C. Anguera; Adam Williams; E. John Wherry; Jorge Henao-Mejia. The long noncoding RNAMorrbidregulates CD8 T cells in response to viral infection. Proceedings of the National Academy of Sciences 2019, 116, 201819457 -11925.
AMA StyleJonathan J. Kotzin, Fany Iseka, Jasmine Wright, Megha G. Basavappa, Megan L. Clark, Mohammed-Alkhatim Ali, Mohamed S. Abdel-Hakeem, Tanner F. Robertson, Walter Mowel, Leonel Joannas, Vanessa D. Neal, Sean Spencer, Camille M. Syrett, Montserrat C. Anguera, Adam Williams, E. John Wherry, Jorge Henao-Mejia. The long noncoding RNAMorrbidregulates CD8 T cells in response to viral infection. Proceedings of the National Academy of Sciences. 2019; 116 (24):201819457-11925.
Chicago/Turabian StyleJonathan J. Kotzin; Fany Iseka; Jasmine Wright; Megha G. Basavappa; Megan L. Clark; Mohammed-Alkhatim Ali; Mohamed S. Abdel-Hakeem; Tanner F. Robertson; Walter Mowel; Leonel Joannas; Vanessa D. Neal; Sean Spencer; Camille M. Syrett; Montserrat C. Anguera; Adam Williams; E. John Wherry; Jorge Henao-Mejia. 2019. "The long noncoding RNAMorrbidregulates CD8 T cells in response to viral infection." Proceedings of the National Academy of Sciences 116, no. 24: 201819457-11925.
Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
Laura M. McLane; Mohamed Abdel Hakeem; E. John Wherry. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annual Review of Immunology 2019, 37, 457 -495.
AMA StyleLaura M. McLane, Mohamed Abdel Hakeem, E. John Wherry. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annual Review of Immunology. 2019; 37 (1):457-495.
Chicago/Turabian StyleLaura M. McLane; Mohamed Abdel Hakeem; E. John Wherry. 2019. "CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer." Annual Review of Immunology 37, no. 1: 457-495.
Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.
Mohamed S. Abdel-Hakeem. Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries. Viruses 2019, 11, 106 .
AMA StyleMohamed S. Abdel-Hakeem. Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries. Viruses. 2019; 11 (2):106.
Chicago/Turabian StyleMohamed S. Abdel-Hakeem. 2019. "Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries." Viruses 11, no. 2: 106.
Hepatitis C virus (HCV) affects more than 268,000 people in Canada. Both the Canadian Institutes of Health Research and the Public Health Agency of Canada recognize the significant impact of HCV-related liver diseases and supported the establishment of a national hepatitis C research network, the Canadian Network on Hepatitis C (CanHepC). Interferon-free direct-acting antiviral regimens lead to more than 95% cure rates in almost all patients with well-tolerated short-course therapy. However, the goal of eliminating HCV in Canada cannot be fully realized until we overcome the financial, geographical, cultural, and social barriers that affect the entire continuum of care from diagnosis and linkage to care through treatment and prevention of new and reinfections. Current practices face difficulties in reversing HCV-induced immunological defects, expanding treatment to neglected communities, combating reinfections and co-infections, and expediting and simplifying the processes of diagnosis and treatment. As part of its knowledge translation mandate, CanHepC has organized the annual Canadian symposium on hepatitis C since 2012. The theme of this year’s symposium, “Toward Elimination of HCV: How to Get There?” focused on identifying the requirements of our therapeutic strategies and health policies for the elimination of HCV in Canada.
Michael L Cheng; Mohamed S Abdel-Hakeem; Sophie E Cousineau; Jason Grebely; Alison D Marshall; Sahar Saeed; Selena M Sagan; Naglaa H Shoukry; Jordan J Feld; Sonya A MacParland. The 7th Canadian Symposium on Hepatitis C Virus: “Toward Elimination of HCV: How to Get There”. Canadian Liver Journal 2018, 1, 139 -152.
AMA StyleMichael L Cheng, Mohamed S Abdel-Hakeem, Sophie E Cousineau, Jason Grebely, Alison D Marshall, Sahar Saeed, Selena M Sagan, Naglaa H Shoukry, Jordan J Feld, Sonya A MacParland. The 7th Canadian Symposium on Hepatitis C Virus: “Toward Elimination of HCV: How to Get There”. Canadian Liver Journal. 2018; 1 (3):139-152.
Chicago/Turabian StyleMichael L Cheng; Mohamed S Abdel-Hakeem; Sophie E Cousineau; Jason Grebely; Alison D Marshall; Sahar Saeed; Selena M Sagan; Naglaa H Shoukry; Jordan J Feld; Sonya A MacParland. 2018. "The 7th Canadian Symposium on Hepatitis C Virus: “Toward Elimination of HCV: How to Get There”." Canadian Liver Journal 1, no. 3: 139-152.
Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated with two different glycogen synthase kinase (GSK3)-β inhibitors; AR-A014418 and lithium chloride. Intra- and extracellular HCV virions and specific infectivity was determined using real-time RT-PCR and TCID50, and changes in lipid production were identified by enzyme-linked immunoassay and mass spectrometry analyses. Similarly, effect on two HCV replicon cells were identified by the luciferase activity. Although there was limited effect on virus replication in Huh7.5 cells and replicons, Huh7.5 cells treated with GSK3β inhibitors produced significantly less viral particles in comparison to untreated cells. In addition, the treated cells synthesized significantly lower amounts of ApoB and trapped the ApoE lipoproteins in the cells. In conclusion, our study suggests that GSK3β plays a pivotal role in HCV virion assembly and release mediated in part through inhibition of apolipoprotein synthesis.
Mohammed A. Sarhan; Mohamed S. Abdel-Hakeem; Andrew L. Mason; D. Lorne Tyrrell; Michael Houghton. Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism. Scientific Reports 2017, 7, 1 -12.
AMA StyleMohammed A. Sarhan, Mohamed S. Abdel-Hakeem, Andrew L. Mason, D. Lorne Tyrrell, Michael Houghton. Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism. Scientific Reports. 2017; 7 (1):1-12.
Chicago/Turabian StyleMohammed A. Sarhan; Mohamed S. Abdel-Hakeem; Andrew L. Mason; D. Lorne Tyrrell; Michael Houghton. 2017. "Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism." Scientific Reports 7, no. 1: 1-12.
The dynamics of the memory CD8 T cell receptor (TCR) repertoire upon virus re-exposure and factors governing the selection of TCR clonotypes conferring protective immunity in real life settings are poorly understood. Here, we examined the dynamics and functionality of the virus-specific memory CD8 TCR repertoire before, during and after hepatitis C virus (HCV) reinfection in patients who spontaneously resolved two consecutive infections (SR/SR) and patients who resolved a primary but failed to clear a subsequent infection (SR/CI). The TCR repertoire was narrower prior to reinfection in the SR/SR group as compared to the SR/CI group and became more focused upon reinfection. CD8 T cell clonotypes expanding upon re-exposure and associated with protection from viral persistence were recruited from the memory T cell pool. Individual CD8 T cell lines generated from the SR/SR group exhibited higher functional avidity and polyfunctionality as compared to cell lines from the SR/CI group. Our results suggest that protection from viral persistence upon HCV reinfection is associated with focusing of the HCV-specific CD8 memory T cell repertoire from which established cell lines showed high functional avidity. These findings are applicable to vaccination strategies aiming at shaping the protective human T cell repertoire.
Mohamed S. Abdel-Hakeem; Maude Boisvert; Julie Bruneau; Hugo Soudeyns; Naglaa H. Shoukry. Selective expansion of high functional avidity memory CD8 T cell clonotypes during hepatitis C virus reinfection and clearance. PLOS Pathogens 2017, 13, e1006191 .
AMA StyleMohamed S. Abdel-Hakeem, Maude Boisvert, Julie Bruneau, Hugo Soudeyns, Naglaa H. Shoukry. Selective expansion of high functional avidity memory CD8 T cell clonotypes during hepatitis C virus reinfection and clearance. PLOS Pathogens. 2017; 13 (2):e1006191.
Chicago/Turabian StyleMohamed S. Abdel-Hakeem; Maude Boisvert; Julie Bruneau; Hugo Soudeyns; Naglaa H. Shoukry. 2017. "Selective expansion of high functional avidity memory CD8 T cell clonotypes during hepatitis C virus reinfection and clearance." PLOS Pathogens 13, no. 2: e1006191.
The innate and adaptive immune systems fail to control HCV infection in the majority of infected individuals. HCV is an ssRNA virus, which suggests a role for Toll-like receptors (TLRs) 7 and 8 in initiating the anti-viral response. Here we demonstrate that HCV genomic RNA harbours specific sequences that initiate an anti-HCV immune response through TLR7 and TLR8 in various antigen presenting cells. Conversely, HCV particles are detected by macrophages, but not by monocytes and DCs, through a TLR7/8 dependent mechanism; this leads to chloroquine sensitive production of pro-inflammatory cytokines including IL-1β, while the antiviral type I Interferon response is not triggered in these cells. Antibodies to DC-SIGN, a c-type lectin selectively expressed by macrophages but not pDCs or mDCs, block the production of cytokines. Novel anti-HCV vaccination strategies should target the induction of TLR7/8 stimulation in APCs in order to establish potent immune responses against HCV.
Yuwei Zhang; Mohamed El-Far; Franck P. Dupuy; Mohamed Abdel Hakeem; Zhong He; Francesco Andrea Procopio; Yu Shi; Elias K. Haddad; Petronela Ancuta; Rafick-Pierre Sekaly; Elias A. Said. HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses. Scientific Reports 2016, 6, 29447 .
AMA StyleYuwei Zhang, Mohamed El-Far, Franck P. Dupuy, Mohamed Abdel Hakeem, Zhong He, Francesco Andrea Procopio, Yu Shi, Elias K. Haddad, Petronela Ancuta, Rafick-Pierre Sekaly, Elias A. Said. HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses. Scientific Reports. 2016; 6 (1):29447.
Chicago/Turabian StyleYuwei Zhang; Mohamed El-Far; Franck P. Dupuy; Mohamed Abdel Hakeem; Zhong He; Francesco Andrea Procopio; Yu Shi; Elias K. Haddad; Petronela Ancuta; Rafick-Pierre Sekaly; Elias A. Said. 2016. "HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses." Scientific Reports 6, no. 1: 29447.
Background & Aims Development of a vaccine against hepatitis C virus (HCV) has been hindered by our limited understanding of immune correlates of protection during real-life exposure to the virus. We studied the immune response during HCV reinfection. Methods We analyzed blood samples from participants in the Montreal Acute Hepatitis C Injection Drug User Cohort Study who were reinfected with HCV from 2009 to 2012. Five patients spontaneously resolved their second infection and 4 developed chronic infections. We monitored the phenotypic and functional dynamics of HCV-specific memory T cell responses in all subjects during natural re-exposure and re-infection. Results Populations of CD4+ and CD8+ T cells with HCV-specific polyfunctional memory were expanded in all 5 individuals who resolved 2 successive HCV infections. We detected CD127hi HCV-specific memory CD8+ T cells before reinfection regardless of a subject's ability to clear subsequent infections. Protection against viral persistence was associated with the expansion of a CD127neg, PD1lo effector memory T cells at the peak of the response. We also observed broadening of T-cell response, indicating generation of de novo T-cell responses. The 4 individuals who failed to clear their subsequent infection had limited expansion of HCV-specific CD4+ and CD8+ memory T cells and expressed variable levels of the exhaustion marker PD1 on HCV-specific CD8+ T cells. Dominant epitope regions of HCV strains isolated from patients with persistent reinfection had sequence variations that were not recognized by the pre-existing memory T cells. Conclusions Protection from persistent HCV reinfection depends on the magnitude, breadth, and quality of the HCV-specific memory T-cell response. Sequence homology among viruses and ability of T cells to recognize multiple strains of HCV are critical determinants of protective memory.
Mohamed Abdel Hakeem; Nathalie Bédard; Donald Murphy; Julie Bruneau; Naglaa H. Shoukry. Signatures of Protective Memory Immune Responses During Hepatitis C Virus Reinfection. Gastroenterology 2014, 147, 870 -881.e8.
AMA StyleMohamed Abdel Hakeem, Nathalie Bédard, Donald Murphy, Julie Bruneau, Naglaa H. Shoukry. Signatures of Protective Memory Immune Responses During Hepatitis C Virus Reinfection. Gastroenterology. 2014; 147 (4):870-881.e8.
Chicago/Turabian StyleMohamed Abdel Hakeem; Nathalie Bédard; Donald Murphy; Julie Bruneau; Naglaa H. Shoukry. 2014. "Signatures of Protective Memory Immune Responses During Hepatitis C Virus Reinfection." Gastroenterology 147, no. 4: 870-881.e8.
The majority of individuals who become acutely infected with hepatitis C virus (HCV) develop chronic infection and suffer from progressive liver damage while approximately 25% are able to eliminate the virus spontaneously. Despite the recent introduction of new direct-acting antivirals (DAAs), there is still no vaccine for HCV. As a result, new infections and reinfections will remain a problem in developing countries and among high risk populations like injection drug users (IDUs) who have limited access to treatment and who continue to be exposed to the virus. The outcome of acute HCV is determined by the interplay between the host genetics, the virus and the virus-specific immune response. Studies in humans and chimpanzees have demonstrated the essential role of HCV-specific CD4 and CD8 T cell responses in protection against viral persistence. Recent data suggest that antibody responses play a more important role than what was previously thought. Individuals who spontaneously resolve acute HCV infection develop long-lived memory T cells and are less likely to become persistently infected upon re-exposure. New studies examining high risk cohorts are identifying correlates of protection during real life exposures and reinfections. In this review, we discuss correlates of protective immunity during acute HCV and upon reexposure. We draw parallels between HCV and the current knowledge about protective memory in other models of chronic viral infections. Finally, we discuss some of the yet unresolved questions about key correlates of protection and their relevance for vaccine development against HCV.
Mohamed Abdel Hakeem; Naglaa H. Shoukry. Protective Immunity Against Hepatitis C: Many Shades of Gray. Frontiers in Immunology 2014, 5, 274 .
AMA StyleMohamed Abdel Hakeem, Naglaa H. Shoukry. Protective Immunity Against Hepatitis C: Many Shades of Gray. Frontiers in Immunology. 2014; 5 ():274.
Chicago/Turabian StyleMohamed Abdel Hakeem; Naglaa H. Shoukry. 2014. "Protective Immunity Against Hepatitis C: Many Shades of Gray." Frontiers in Immunology 5, no. : 274.
Early alpha interferon (IFN-α) therapy against hepatitis C virus (HCV) rescues polyfunctional, virus-specific memory CD8 + T cells, but whether immune restoration is possible during late therapy remains controversial. We compared immune restoration of HCV-specific memory T cells in patients who cleared HCV infection spontaneously and following early or late IFN therapy. Multifunctional CD4 + and CD8 + memory T cells were detected in spontaneous resolvers and in individuals treated early following an acute infection. In contrast, limited responses were detected in patients treated during chronic infection, and the phenotype of HCV-specific cells was influenced by autologous viral sequences. Our data suggest that irreversible damage to the HCV-specific memory T-cell response is associated with chronic HCV infection.
Mohamed S. Abdel-Hakeem; Nathalie Bédard; Gamal Badr; Mario Ostrowski; Rafick P. Sékaly; Julie Bruneau; Bernard Willems; E. Jenny Heathcote; Naglaa H. Shoukry. Comparison of Immune Restoration in Early versus Late Alpha Interferon Therapy against Hepatitis C Virus. Journal of Virology 2010, 84, 10429 -10435.
AMA StyleMohamed S. Abdel-Hakeem, Nathalie Bédard, Gamal Badr, Mario Ostrowski, Rafick P. Sékaly, Julie Bruneau, Bernard Willems, E. Jenny Heathcote, Naglaa H. Shoukry. Comparison of Immune Restoration in Early versus Late Alpha Interferon Therapy against Hepatitis C Virus. Journal of Virology. 2010; 84 (19):10429-10435.
Chicago/Turabian StyleMohamed S. Abdel-Hakeem; Nathalie Bédard; Gamal Badr; Mario Ostrowski; Rafick P. Sékaly; Julie Bruneau; Bernard Willems; E. Jenny Heathcote; Naglaa H. Shoukry. 2010. "Comparison of Immune Restoration in Early versus Late Alpha Interferon Therapy against Hepatitis C Virus." Journal of Virology 84, no. 19: 10429-10435.
The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-α) antiviral therapy achieves the highest rate of success when IFN-α is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-γ- and IL-2-producing and CD107a + ) virus-specific CD8 + T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8 + T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-α rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.
Gamal Badr; Nathalie Bédard; Mohamed Abdel Hakeem; Lydie Trautmann; Bernard Willems; Jean-Pierre Villeneuve; Elias K. Haddad; Rafick P. Sékaly; Julie Bruneau; Naglaa H. Shoukry. Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8 + Memory T Cells. Journal of Virology 2008, 82, 10017 -10031.
AMA StyleGamal Badr, Nathalie Bédard, Mohamed Abdel Hakeem, Lydie Trautmann, Bernard Willems, Jean-Pierre Villeneuve, Elias K. Haddad, Rafick P. Sékaly, Julie Bruneau, Naglaa H. Shoukry. Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8 + Memory T Cells. Journal of Virology. 2008; 82 (20):10017-10031.
Chicago/Turabian StyleGamal Badr; Nathalie Bédard; Mohamed Abdel Hakeem; Lydie Trautmann; Bernard Willems; Jean-Pierre Villeneuve; Elias K. Haddad; Rafick P. Sékaly; Julie Bruneau; Naglaa H. Shoukry. 2008. "Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8 + Memory T Cells." Journal of Virology 82, no. 20: 10017-10031.
Mohamed S. Abdel-Hakeem; Nathalie Bedard; Gamal Badr; Mario Ostrowski; Julie Bruneau; Rafick P. Sékaly; Bernard Willems; Jenny E. Heathcote; Naglaa H. Shoukry. 265 Early but not late interferon alpha therapy against hepatitis C rescues polyfunctional CD4+ and CD8+ memory T cells. Cytokine 2008, 43, 306 -307.
AMA StyleMohamed S. Abdel-Hakeem, Nathalie Bedard, Gamal Badr, Mario Ostrowski, Julie Bruneau, Rafick P. Sékaly, Bernard Willems, Jenny E. Heathcote, Naglaa H. Shoukry. 265 Early but not late interferon alpha therapy against hepatitis C rescues polyfunctional CD4+ and CD8+ memory T cells. Cytokine. 2008; 43 (3):306-307.
Chicago/Turabian StyleMohamed S. Abdel-Hakeem; Nathalie Bedard; Gamal Badr; Mario Ostrowski; Julie Bruneau; Rafick P. Sékaly; Bernard Willems; Jenny E. Heathcote; Naglaa H. Shoukry. 2008. "265 Early but not late interferon alpha therapy against hepatitis C rescues polyfunctional CD4+ and CD8+ memory T cells." Cytokine 43, no. 3: 306-307.