Boisvert, M., M. Abdel–Hakeem, J. Bruneau, H. Soudeyns, and N. H. Shoukry, "High avidity and functionality of virus-specific CD8 T cells associated with protection during HCV reinfection ", IMMUNOLOGY 2015, ew Orleans, LA, USA, American Association of Immunologists (AAI), 2015.
Abdel–Hakeem, M. S., O. Khan, E. Stelekati, M. - A. Ali, and E. J. Wherry, "Reprogramming of exhausted T cells following elimination of chronic antigen exposure.", IMMUNOLOGY 2017, Washington, D.C., American Association of Immunologists (AAI), pp. 198.5., 2017.
Sarhan, M. A., M. S. Abdel–Hakeem, A. L. Mason, L. D. Tyrrell, and M. Houghton, "Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism. ", Scientific Reports, vol. 7, pp. 2495, 2017.
Abdel–Hakeem, M. S., M. Boisvert, J. Bruneau, H. Soudeyns, and N. H. Shoukry, "Selective Expansion of High Functional Avidity Memory CD8 T cell Clonotypes during Hepatitis C Virus Reinfection and Clearance", PLOS Pathogens, vol. 13, issue 2, pp. e1006191, 2017.
Abdel-Hakeem, M. S., N. Bédard, G. Badr, M. Ostrowski, J. Bruneau, R. P. Sékaly, B. Willems, J. E. Heathcote, and N. H. Shoukry, Early but not late interferon alpha therapy against hepatitis C rescues polyfunctional CD4+ and CD8+ memory T cells, , Montréal, Québec, CANADA, 2008. conf._proc._my_2008_-_cytokine.pdf
Badr, G., N. Bédard, M. S. Abdel-Hakeem, L. Trautmann, B. Willems, J. - P. Villeneuve, E. K. Haddad, R. P. Sékaly, J. Bruneau, and N. H. Shoukry, "Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8! Memory T Cells", JOURNAL OF VIROLOGY, vol. 82, issue 20, pp. 10017–10031, 2008. AbstractWebsite

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage.
Alpha interferon (IFN-!) antiviral therapy achieves the highest rate of success when IFN-! 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 HCVspecific
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-"- 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-! 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.

Abdel-Hakeem, M. S., N. Bédard, G. Badr, M. Ostrowski, R. P. Sékaly, J. Bruneau, B. Willems, J. E. Heathcote, and N. H. Shoukry, "Comparison of Immune Restoration in Early versus Late Alpha Interferon Therapy against Hepatitis C Virus", JOURNAL OF VIROLOGY, vol. 84, issue 19, pp. 10429–10435, 2010. AbstractWebsite

Early alpha interferon (IFN-!) therapy against hepatitis C virus (HCV) rescues polyfunctional, virusspecific
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.

Abdel-Hakeem, M. S., N. Bédard, D. Murphy, J. Bruneau, and N. H. Shoukry, "Signatures of Protective Memory Immune Responses During Hepatitis C Virus Reinfection", Gastroenterology, vol. 147, pp. 870-881, 2014. Abstractgastro_article_2014-oct.pdfmy_2014_-_gastro_commentary.pdfWebsite

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 reinfection.
RESULTS: Populations of CD4þ and CD8þ 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 CD8þ 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 CD4þ and CD8þ memory T
cells and expressed variable levels of the exhaustion marker PD1
on HCV-specific CD8þ 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.

Abdel-Hakeem, M. S., and N. H. Shoukry, "Protective immunity against hepatitis C: many shades of gray", Frontiers in Immunology, vol. 5, pp. 1-19, 2014. AbstractWebsite

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, 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 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 memoryT cells and are less
likely to become persistently infected upon reexposure. 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.

Zhang, Y., M. El-Far, F. P. Dupuy, M. S. Abdel-Hakeem, Z. He, F. A. Procopio, Y. Shi, E. K. Haddad, P. Ancuta, R. - P. Sekaly, et al., "HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses.", Scientific Reports, vol. 6, pp. 1-13, 2016. AbstractWebsite

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 proinflammatory
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.

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