LFA-3 Plasmid DNA Enhances Ag-Specific Humoral- and Cellular-Mediated Protective Immunity against Herpes Simplex Virus-2 in Vivo: Involvement of CD4+ T Cells in Protection

ABSTRACT Herpes simplex virus (HSV) infections of humans are characterized by intermittent, lytic replication in epithelia. Circulating HSV-specific CD4 T cells express lower levels of preformed cutaneous lymphocyte-associated antigen (CLA), a skin-homing receptor, than do circulating HSV-specific CD8 T cells but, paradoxically, move into infected skin earlier than CD8 cells. Memory CD4 T cells develop strong and selective expression of CLA and E-selectin ligand while responding to HSV antigen in vitro. We now show that interleukin-12, type I interferon, and transforming growth factor beta are each involved in CLA expression by memory HSV type 2 (HSV-2)-specific CD4 T cells in peripheral blood mononuclear cells (PBMC). A reduction of the number of monocytes and dendritic cells from PBMC reduces CLA expression by HSV-2-responsive CD4 lymphoblasts, while their reintroduction restores this phenotype, identifying these cells as possible sources of CLA-promoting cytokines. Plasmacytoid dendritic cells are particularly potent inducers of CLA on HSV-reactive CD4 T cells. These observations are consistent with cooperation between innate and acquired immunity to promote a pattern of homing receptor expression that is physiologically appropriate for trafficking to infected tissues.

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Molecular mechanism for ganciclovir resistance in human T lymphocytes transduced with retroviral vectors carrying the herpes simplex virus thymidine kinase gene

Blood ◽

10.1182/blood.v97.1.122 ◽

2001 ◽

Vol 97 (1) ◽

pp. 122-129 ◽

Cited By ~ 84

Author(s):

Marina I. Garin ◽

Elaine Garrett ◽

Pierre Tiberghien ◽

Jane F. Apperley ◽

David Chalmers ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Marker Gene ◽

Retroviral Vectors ◽

Thymidine Kinase Gene ◽

Kinase Gene ◽

Donor T Cells ◽

Simplex Virus

Abstract The herpes simplex virus thymidine kinase gene type 1 (HSV-Tk) ganciclovir (GCV) system is a novel therapeutic strategy for the modulation of graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation (allo-SCT). Retroviral-mediated gene transfer of the HSV-Tk gene into donor T lymphocytes before allo-SCT may allow their in vivo selective depletion after treatment with GCV. The expression of theHSV-Tk gene was analyzed in vitro in CEM cells, a human lymphoblastoid cell line, transduced with 2 different vectors, each containing the HSV-Tk gene and a selectable marker gene. GCV-resistant clones were identified within the clones expressing the marker gene. Characterization of the molecular events leading to this resistance revealed a 227-bp deletion in the HSV-Tk gene due to the presence of cryptic splice donor and acceptor sites within the HSV-Tk gene sequence. Furthermore, it was confirmed that this deletion was present in human primary T cells transduced with either vector and in 12 patients who received transduced donor T cells, together with a T-cell–depleted allo-SCT. In vivo circulating transduced T cells containing the truncated HSV-Tk gene were identified in all patients immediately after infusion and up to 800 days after transplantation. In patients who received GCV as treatment for GVHD, a progressive increase in the proportion of transduced donor T cells carrying the deleted HSV-Tkgene was observed. These results suggest that the limitations within the HSV-Tk/GCV system can be improved by developing optimized retroviral vectors to ensure maximal killing ofHSV-Tk–transduced cells.

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Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8+T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge

Journal of Virology ◽

10.1128/jvi.02380-14 ◽

2014 ◽

Vol 89 (1) ◽

pp. 83-96 ◽

Cited By ~ 24

Author(s):

Nicolas Çuburu ◽

Kening Wang ◽

Kyle N. Goodman ◽

Yuk Ying Pang ◽

Cynthia D. Thompson ◽

...

Keyword(s):

T Cells ◽

Human Papillomavirus ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Neutralizing Antibodies ◽

Viral Shedding ◽

Monophosphoryl Lipid A ◽

Simplex Virus ◽

Herpes Simplex Virus 2 ◽

Genital Tissue

ABSTRACTNo herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8+T cells that were able to secrete gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8+T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection.IMPORTANCEGenital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection.

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Vaccination with a DNA Vaccine Encoding Herpes Simplex Virus Type 1 VP22 Linked to Antigen Generates Long-Term Antigen-Specific CD8-Positive Memory T Cells and Protective Immunity

Human Gene Therapy ◽

10.1089/104303404772679977 ◽

2004 ◽

Vol 15 (2) ◽

pp. 167-177 ◽

Cited By ~ 46

Author(s):

Tae Woo Kim ◽

Chien-Fu Hung ◽

Jeong Won Kim ◽

Jeremy Juang ◽

Pei-Jer Chen ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Dna Vaccine ◽

Herpes Simplex Virus Type ◽

Protective Immunity ◽

Memory T Cells ◽

Simplex Virus

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In Vitro-Generated Antigen-Specific CD4+ CD25+ Foxp3+ Regulatory T Cells Control the Severity of Herpes Simplex Virus-Induced Ocular Immunoinflammatory Lesions

Journal of Virology ◽

10.1128/jvi.00697-08 ◽

2008 ◽

Vol 82 (14) ◽

pp. 6838-6851 ◽

Cited By ~ 50

Author(s):

Sharvan Sehrawat ◽

Susmit Suvas ◽

Pranita P. Sarangi ◽

Amol Suryawanshi ◽

Barry T. Rouse

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Regulatory T Cells ◽

Inflammatory Disease ◽

Activation Markers ◽

Control Virus ◽

Simplex Virus

ABSTRACT Generating and using regulatory T cells (Tregs) to modulate inflammatory disease represents a valuable approach to therapy but has not yet been applied as a means to control virus-induced immunopathological reactions. In this report, we developed a simplified technique that used unfractionated splenocytes as a precursor population and showed that stimulation under optimized conditions for 5 days with solid-phase anti-CD3 monoclonal antibody in the presence of transforming growth factor β (TGF-β) and interleukin-2 could induce up to 90% of CD4+ T cells to become Foxp3+ and able to mediate suppression in vitro. CD11c+ dendritic cells were intricately involved in the conversion process and, once modified in the presence of TGF-β, could convert Foxp3− CD4+ cells into Foxp3+ CD4+cells by producing TGF-β. The converted cells had undergone cell division, and the majority of them expressed activation markers along with surface molecules that would facilitate their migration into tissue sites. The primary reason for our study was to determine if such in vitro-converted Tregs could be used in vivo to influence the outcome of a virus-induced immunoinflammatory lesion in the eye caused by herpes simplex virus infection. We could show in three separate models of herpetic stromal keratitis that adoptive transfers of in vitro-converted Tregs effectively diminished lesion severity, especially when given in the initial phases of infection. The suppression effect in vivo appeared to be polyspecific. The protocol we have developed could provide a useful additional approach to control virus-induced inflammatory disease.

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