The Experts below are selected from a list of 54 Experts worldwide ranked by ideXlab platform

Lbachir Benmohamed - One of the best experts on this subject based on the ideXlab platform.

  • human asymptomatic epitopes identified from the Herpes Simplex virus tegument protein vp13 14 ul47 preferentially recall polyfunctional effector memory cd44high cd62llow cd8 tem cells and protect humanized hla a 02 01 transgenic mice against ocular h
    Journal of Virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocula
    Journal of virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • therapeutic immunization with a mixture of Herpes Simplex virus type 1 glycoprotein d derived asymptomatic human cd8 t cell epitopes decreases spontaneous ocular shedding in latently infected hla transgenic rabbits association with low frequency of l
    Journal of Immunology, 2015
    Co-Authors: Lbachir Benmohamed, Ruchi Srivastava, Arif A Khan, Anthony B. Nesburn
    Abstract:

    Most blinding ocular herpetic disease is due to reactivation of Herpes Simplex virus type 1 (HSV-1) from latency rather than to primary acute infection. No Herpes Simplex Vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular Herpes to assess the therapeutic efficacy of a therapeutic Vaccine based on HSV-1 gD epitopes that are mainly recognized by CD8 + T cells from “naturally” protected HLA-A*02:01 positive, HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical Herpes disease). Three ASYMP CD8 + T cell epitopes (gD 53-61 , gD 70-78 and gD 278-286 ) were linked with a promiscuous CD4 + T-cell epitope (gD 287-317 ) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an N e -palmitoyl-lysine moiety, a toll like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide Vaccines. Latently infected HLA-Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide Vaccines, delivered as eye drops in sterile PBS. The ASYMP therapeutic vaccination: ( i ) significantly reduced HSV-1 shedding detected in tears; ( ii ) boosted the number and function of local HSV-1-specific CD8 + T cells; and ( iii ) was associated with fewer exhausted HSV-1 gD-specific PD-1 + TIM-3 + CD8 + T-cells. The results underscore the potential of an ASYMP CD8 + T cell epitope-based therapeutic Vaccine strategy against recurrent ocular Herpes.

  • The challenges and opportunities for the development of a T-cell epitope-based Herpes Simplex Vaccine.
    Vaccine, 2014
    Co-Authors: Tiffany Kuo, Tina Badakhshan, Christine Wang, Sravya Chilukuri, Lbachir Benmohamed
    Abstract:

    Abstract Herpes Simplex virus type 1 and type 2 (HSV-1 & HSV-2) infections have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a billion individuals worldwide. HSV-1 infections are predominant than HSV-2 infections and cause potentially blinding ocular Herpes, oro-facial Herpes and encephalitis. HSV-2 infections cause painful genital Herpes, encephalitis, and death in newborns. While prophylactic and therapeutic HSV Vaccines remain urgently needed for centuries, their development has been difficult. During the most recent National Institute of Health (NIH) workshop titled “ Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities” , basic researchers, funding agencies, and pharmaceutical representatives gathered: ( i ) to assess the status of Herpes Vaccine research; and ( ii ) to identify the gaps and propose alternative approaches in developing a safe and efficient Herpes Vaccine. One “common denominator” among previously failed clinical Herpes Vaccine trials is that they either used a whole virus or a whole viral protein, which contain both “pathogenic symptomatic” and “protective asymptomatic” antigens and epitopes. In this report, we continue to advocate developing “asymptomatic” epitope-based sub-unit Vaccine strategies that selectively incorporate “protective asymptomatic” epitopes which: ( i ) are exclusively recognized by effector memory CD4 + and CD8 + T cells (T EM cells) from “naturally” protected seropositive asymptomatic individuals; and ( ii ) protect human leukocyte antigen (HLA) transgenic animal models of ocular and genital Herpes. We review the role of animal models in Herpes Vaccine development and discuss their current status, challenges, and prospects.

  • Future of an ‘asymptomatic’ T-cell epitope-based therapeutic Herpes Simplex Vaccine
    Future virology, 2012
    Co-Authors: Xavier Dervillez, Chetan Gottimukkala, Khaled W. Kabbara, Chelsea Nguyen, Tina Badakhshan, Sarah M Kim, Anthony B. Nesburn, Steven L. Wechsler, Lbachir Benmohamed
    Abstract:

    Considering the limited success of the recent Herpes clinical Vaccine trial [1], new Vaccine strategies are needed. Infections with Herpes Simplex virus type 1 and type 2 (HSV-1 & HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different Herpes epitopes. This finding breaks new ground and opens new doors to assess a new Vaccine strategy: mucosal immunization with HSV-1 & HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as "asymptomatic" protective epitopes") could boost local and systemic "natural" protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging "asymptomatic" T cell epitope-based mucosal Vaccine strategy to decrease recurrent herpetic disease.

Ruchi Srivastava - One of the best experts on this subject based on the ideXlab platform.

  • human asymptomatic epitopes identified from the Herpes Simplex virus tegument protein vp13 14 ul47 preferentially recall polyfunctional effector memory cd44high cd62llow cd8 tem cells and protect humanized hla a 02 01 transgenic mice against ocular h
    Journal of Virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocula
    Journal of virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • therapeutic immunization with a mixture of Herpes Simplex virus 1 glycoprotein d derived asymptomatic human cd8 t cell epitopes decreases spontaneous ocular shedding in latently infected hla transgenic rabbits association with low frequency of local
    Journal of Virology, 2015
    Co-Authors: Arif A Khan, Anthony B. Nesburn, Ruchi Srivastava, Aziz Alami Chentoufi, Roger Geertsema, Nhi Thi Uyen Thai, Gargi Dasgupta, Nelson Osorio, Mina Kalantari, Steven L. Wechsler
    Abstract:

    Most blinding ocular herpetic disease is due to reactivation of Herpes Simplex virus 1 (HSV-1) from latency rather than to primary acute infection. No Herpes Simplex Vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular Herpes to assess the efficacy of a therapeutic Vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8+ T cells from “naturally” protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical Herpes disease). Three ASYMP CD8+ T-cell epitopes (gD53–61, gD70–78, and gD278–286) were linked with a promiscuous CD4+ T-cell epitope (gD287–317) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an Ne-palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide Vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide Vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8+ T cells that prevent HSV-1 reactivation ex vivo from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8+ T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1+ TIM-3+ CD8+ T cells. The results underscore the potential of an ASYMP CD8+ T-cell epitope-based therapeutic Vaccine strategy against recurrent ocular Herpes. IMPORTANCE Seventy percent to 90% of adults harbor Herpes Simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most blinding herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. To date, there is no licensed therapeutic Vaccine that can effectively stop or reduce HSV-1 reactivation from latently infected sensory ganglia and the subsequent shedding in tears. In the present study, we demonstrated that topical ocular therapeutic vaccination of latently infected HLA transgenic rabbits with a lipopeptide Vaccine that contains exclusively human “asymptomatic” CD8+ T-cell epitopes successfully decreased spontaneous HSV-1 reactivation, as judged by a significant reduction in spontaneous shedding in tears. The findings should guide the clinical development of a safe and effective T-cell-based therapeutic Herpes Vaccine.

  • therapeutic immunization with a mixture of Herpes Simplex virus type 1 glycoprotein d derived asymptomatic human cd8 t cell epitopes decreases spontaneous ocular shedding in latently infected hla transgenic rabbits association with low frequency of l
    Journal of Immunology, 2015
    Co-Authors: Lbachir Benmohamed, Ruchi Srivastava, Arif A Khan, Anthony B. Nesburn
    Abstract:

    Most blinding ocular herpetic disease is due to reactivation of Herpes Simplex virus type 1 (HSV-1) from latency rather than to primary acute infection. No Herpes Simplex Vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular Herpes to assess the therapeutic efficacy of a therapeutic Vaccine based on HSV-1 gD epitopes that are mainly recognized by CD8 + T cells from “naturally” protected HLA-A*02:01 positive, HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical Herpes disease). Three ASYMP CD8 + T cell epitopes (gD 53-61 , gD 70-78 and gD 278-286 ) were linked with a promiscuous CD4 + T-cell epitope (gD 287-317 ) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an N e -palmitoyl-lysine moiety, a toll like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide Vaccines. Latently infected HLA-Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide Vaccines, delivered as eye drops in sterile PBS. The ASYMP therapeutic vaccination: ( i ) significantly reduced HSV-1 shedding detected in tears; ( ii ) boosted the number and function of local HSV-1-specific CD8 + T cells; and ( iii ) was associated with fewer exhausted HSV-1 gD-specific PD-1 + TIM-3 + CD8 + T-cells. The results underscore the potential of an ASYMP CD8 + T cell epitope-based therapeutic Vaccine strategy against recurrent ocular Herpes.

Anthony B. Nesburn - One of the best experts on this subject based on the ideXlab platform.

  • human asymptomatic epitopes identified from the Herpes Simplex virus tegument protein vp13 14 ul47 preferentially recall polyfunctional effector memory cd44high cd62llow cd8 tem cells and protect humanized hla a 02 01 transgenic mice against ocular h
    Journal of Virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocula
    Journal of virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • therapeutic immunization with a mixture of Herpes Simplex virus 1 glycoprotein d derived asymptomatic human cd8 t cell epitopes decreases spontaneous ocular shedding in latently infected hla transgenic rabbits association with low frequency of local
    Journal of Virology, 2015
    Co-Authors: Arif A Khan, Anthony B. Nesburn, Ruchi Srivastava, Aziz Alami Chentoufi, Roger Geertsema, Nhi Thi Uyen Thai, Gargi Dasgupta, Nelson Osorio, Mina Kalantari, Steven L. Wechsler
    Abstract:

    Most blinding ocular herpetic disease is due to reactivation of Herpes Simplex virus 1 (HSV-1) from latency rather than to primary acute infection. No Herpes Simplex Vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular Herpes to assess the efficacy of a therapeutic Vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8+ T cells from “naturally” protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical Herpes disease). Three ASYMP CD8+ T-cell epitopes (gD53–61, gD70–78, and gD278–286) were linked with a promiscuous CD4+ T-cell epitope (gD287–317) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an Ne-palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide Vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide Vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8+ T cells that prevent HSV-1 reactivation ex vivo from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8+ T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1+ TIM-3+ CD8+ T cells. The results underscore the potential of an ASYMP CD8+ T-cell epitope-based therapeutic Vaccine strategy against recurrent ocular Herpes. IMPORTANCE Seventy percent to 90% of adults harbor Herpes Simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most blinding herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. To date, there is no licensed therapeutic Vaccine that can effectively stop or reduce HSV-1 reactivation from latently infected sensory ganglia and the subsequent shedding in tears. In the present study, we demonstrated that topical ocular therapeutic vaccination of latently infected HLA transgenic rabbits with a lipopeptide Vaccine that contains exclusively human “asymptomatic” CD8+ T-cell epitopes successfully decreased spontaneous HSV-1 reactivation, as judged by a significant reduction in spontaneous shedding in tears. The findings should guide the clinical development of a safe and effective T-cell-based therapeutic Herpes Vaccine.

  • therapeutic immunization with a mixture of Herpes Simplex virus type 1 glycoprotein d derived asymptomatic human cd8 t cell epitopes decreases spontaneous ocular shedding in latently infected hla transgenic rabbits association with low frequency of l
    Journal of Immunology, 2015
    Co-Authors: Lbachir Benmohamed, Ruchi Srivastava, Arif A Khan, Anthony B. Nesburn
    Abstract:

    Most blinding ocular herpetic disease is due to reactivation of Herpes Simplex virus type 1 (HSV-1) from latency rather than to primary acute infection. No Herpes Simplex Vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular Herpes to assess the therapeutic efficacy of a therapeutic Vaccine based on HSV-1 gD epitopes that are mainly recognized by CD8 + T cells from “naturally” protected HLA-A*02:01 positive, HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical Herpes disease). Three ASYMP CD8 + T cell epitopes (gD 53-61 , gD 70-78 and gD 278-286 ) were linked with a promiscuous CD4 + T-cell epitope (gD 287-317 ) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an N e -palmitoyl-lysine moiety, a toll like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide Vaccines. Latently infected HLA-Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide Vaccines, delivered as eye drops in sterile PBS. The ASYMP therapeutic vaccination: ( i ) significantly reduced HSV-1 shedding detected in tears; ( ii ) boosted the number and function of local HSV-1-specific CD8 + T cells; and ( iii ) was associated with fewer exhausted HSV-1 gD-specific PD-1 + TIM-3 + CD8 + T-cells. The results underscore the potential of an ASYMP CD8 + T cell epitope-based therapeutic Vaccine strategy against recurrent ocular Herpes.

  • Future of an ‘asymptomatic’ T-cell epitope-based therapeutic Herpes Simplex Vaccine
    Future virology, 2012
    Co-Authors: Xavier Dervillez, Chetan Gottimukkala, Khaled W. Kabbara, Chelsea Nguyen, Tina Badakhshan, Sarah M Kim, Anthony B. Nesburn, Steven L. Wechsler, Lbachir Benmohamed
    Abstract:

    Considering the limited success of the recent Herpes clinical Vaccine trial [1], new Vaccine strategies are needed. Infections with Herpes Simplex virus type 1 and type 2 (HSV-1 & HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different Herpes epitopes. This finding breaks new ground and opens new doors to assess a new Vaccine strategy: mucosal immunization with HSV-1 & HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as "asymptomatic" protective epitopes") could boost local and systemic "natural" protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging "asymptomatic" T cell epitope-based mucosal Vaccine strategy to decrease recurrent herpetic disease.

Arif A Khan - One of the best experts on this subject based on the ideXlab platform.

  • human asymptomatic epitopes identified from the Herpes Simplex virus tegument protein vp13 14 ul47 preferentially recall polyfunctional effector memory cd44high cd62llow cd8 tem cells and protect humanized hla a 02 01 transgenic mice against ocular h
    Journal of Virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocula
    Journal of virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • therapeutic immunization with a mixture of Herpes Simplex virus 1 glycoprotein d derived asymptomatic human cd8 t cell epitopes decreases spontaneous ocular shedding in latently infected hla transgenic rabbits association with low frequency of local
    Journal of Virology, 2015
    Co-Authors: Arif A Khan, Anthony B. Nesburn, Ruchi Srivastava, Aziz Alami Chentoufi, Roger Geertsema, Nhi Thi Uyen Thai, Gargi Dasgupta, Nelson Osorio, Mina Kalantari, Steven L. Wechsler
    Abstract:

    Most blinding ocular herpetic disease is due to reactivation of Herpes Simplex virus 1 (HSV-1) from latency rather than to primary acute infection. No Herpes Simplex Vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular Herpes to assess the efficacy of a therapeutic Vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8+ T cells from “naturally” protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical Herpes disease). Three ASYMP CD8+ T-cell epitopes (gD53–61, gD70–78, and gD278–286) were linked with a promiscuous CD4+ T-cell epitope (gD287–317) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an Ne-palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide Vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide Vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8+ T cells that prevent HSV-1 reactivation ex vivo from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8+ T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1+ TIM-3+ CD8+ T cells. The results underscore the potential of an ASYMP CD8+ T-cell epitope-based therapeutic Vaccine strategy against recurrent ocular Herpes. IMPORTANCE Seventy percent to 90% of adults harbor Herpes Simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most blinding herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. To date, there is no licensed therapeutic Vaccine that can effectively stop or reduce HSV-1 reactivation from latently infected sensory ganglia and the subsequent shedding in tears. In the present study, we demonstrated that topical ocular therapeutic vaccination of latently infected HLA transgenic rabbits with a lipopeptide Vaccine that contains exclusively human “asymptomatic” CD8+ T-cell epitopes successfully decreased spontaneous HSV-1 reactivation, as judged by a significant reduction in spontaneous shedding in tears. The findings should guide the clinical development of a safe and effective T-cell-based therapeutic Herpes Vaccine.

  • therapeutic immunization with a mixture of Herpes Simplex virus type 1 glycoprotein d derived asymptomatic human cd8 t cell epitopes decreases spontaneous ocular shedding in latently infected hla transgenic rabbits association with low frequency of l
    Journal of Immunology, 2015
    Co-Authors: Lbachir Benmohamed, Ruchi Srivastava, Arif A Khan, Anthony B. Nesburn
    Abstract:

    Most blinding ocular herpetic disease is due to reactivation of Herpes Simplex virus type 1 (HSV-1) from latency rather than to primary acute infection. No Herpes Simplex Vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular Herpes to assess the therapeutic efficacy of a therapeutic Vaccine based on HSV-1 gD epitopes that are mainly recognized by CD8 + T cells from “naturally” protected HLA-A*02:01 positive, HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical Herpes disease). Three ASYMP CD8 + T cell epitopes (gD 53-61 , gD 70-78 and gD 278-286 ) were linked with a promiscuous CD4 + T-cell epitope (gD 287-317 ) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an N e -palmitoyl-lysine moiety, a toll like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide Vaccines. Latently infected HLA-Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide Vaccines, delivered as eye drops in sterile PBS. The ASYMP therapeutic vaccination: ( i ) significantly reduced HSV-1 shedding detected in tears; ( ii ) boosted the number and function of local HSV-1-specific CD8 + T cells; and ( iii ) was associated with fewer exhausted HSV-1 gD-specific PD-1 + TIM-3 + CD8 + T-cells. The results underscore the potential of an ASYMP CD8 + T cell epitope-based therapeutic Vaccine strategy against recurrent ocular Herpes.

Tiffany T Pham - One of the best experts on this subject based on the ideXlab platform.

  • human asymptomatic epitopes identified from the Herpes Simplex virus tegument protein vp13 14 ul47 preferentially recall polyfunctional effector memory cd44high cd62llow cd8 tem cells and protect humanized hla a 02 01 transgenic mice against ocular h
    Journal of Virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.

  • Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocula
    Journal of virology, 2017
    Co-Authors: Ruchi Srivastava, Anthony B. Nesburn, Arif A Khan, Sumit Garg, Sabrina A Syed, Julie N Furness, Hawa Vahed, Tiffany T Pham, Lbachir Benmohamed
    Abstract:

    ABSTRACT Herpes Simplex virus 1 (HSV-1) infection is widespread among humans. The HSV-1 virion protein 13/14 (VP13/14), also known as UL47, is a tegument antigen targeted by CD8 + T cells from HSV-seropositive individuals. However, whether VP13/14-specific CD8 + T cells play a role in the natural protection seen in asymptomatic (ASYMP) individuals (individuals who have never had a clinical herpetic disease) has not been elucidated. Using predictive computer-assisted algorithms, we identified 10 potential HLA-A*02:01-restricted CD8 + T-cell epitopes from the 693-amino-acid sequence of the VP13/14 protein. Three out of 10 epitopes exhibited a high to moderate affinity of binding to soluble HLA-A*02:01 molecules. The phenotype and function of CD8 + T cells specific for each epitope were compared in HLA-A*02:01-positive ASYMP individuals and symptomatic (SYMP) individuals (individuals who have frequent clinical herpetic diseases) using determination of a combination of tetramer frequency and the levels of granzyme B, granzyme K, perforin, gamma interferon, tumor necrosis factor alpha, and interleukin-2 production and CD107 a/b cytotoxic degranulation. High frequencies of multifunctional CD8 + T cells directed against three epitopes, VP13/14 from amino acids 286 to 294 (VP13/14 286–294 ), VP13/14 from amino acids 504 to 512 (VP13/14 504–512 ), and VP13/14 from amino acids 544 to 552 (VP13/14 544–552 ), were detected in ASYMP individuals, while only low frequencies were detected in SYMP individuals. The three epitopes also predominantly recalled more CD45RA low CD44 high CCR7 low CD62L low CD8 + effector memory T cells (T EM cells) in ASYMP individuals than SYMP individuals. Moreover, immunization of HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T EM cells associated with strong protective immunity against ocular Herpesvirus infection and disease. Our findings outline the phenotypic and functional features of protective HSV-specific CD8 + T cells that should guide the development of a safe and effective T-cell-based Herpes Simplex Vaccine. IMPORTANCE Although most Herpes Simplex virus 1 (HSV-1)-infected individuals shed the virus in their body fluids following reactivation from latently infected sensory ganglia, the majority never develop a recurrent herpetic disease and remain asymptomatic (ASYMP). In contrast, small proportions of individuals are symptomatic (SYMP) and develop frequent bouts of recurrent disease. The present study demonstrates that naturally protected ASYMP individuals have a higher frequency of effector memory CD8 + T cells (CD8 + T EM cells) specific to three epitopes derived from the HSV-1 tegument protein VP13/14 (VP13/14 286–294 ,VP13/14 504–512 , and VP13/14 544–552 ) than SYMP patients. Moreover, immunization of humanized HLA-A*02:01 transgenic mice with the three CD8 + T EM -cell epitopes from ASYMP individuals induced robust and polyfunctional HSV-specific CD8 + T cells associated with strong protective immunity against ocular Herpesvirus infection and disease. The findings support the emerging concept of the development of a safe and effective asymptomatic Herpes Simplex Vaccine that is selectively based on CD8 + T-cell epitopes from ASYMP individuals.