Coinfection with Herpes Simplex Virus Type 2 Is Associated with Reduced HIV‐Specific T Cell Responses and Systemic Immune Activation

T-cell recognition of the secreted and membrane-bound portions of the herpes simplex virus type 2 (HSV-2) glycoprotein G (sgG-2 and mgG-2, respectively) was compared in symptomatic and asymptomatic HSV-2-infected individuals and in HSV-2-seronegative controls and the responses with HSV-1 glycoproteins C and E (gC-1 and gE-1) were compared. CD4+ T cells from HSV-2-infected individuals specifically recognized both sgG-2 and mgG-2, whereas HSV-1-infected and HSV-seronegative controls did not respond to these glycoproteins. The responses to gC-1 and gE-1, on the other hand, were not type specific, as blood mononuclear cells from both HSV-1- and HSV-2-infected individuals responded in vitro. There was an association between the status of the infection (symptomatic versus asymptomatic) and the CD4+ T-cell responsiveness. Symptomatic HSV-2-seropositive individuals responded with significantly lower Th1 cytokine production to sgG-2 and mgG-2 than did asymptomatic HSV-2-infected carriers, especially within the HSV-1-negative cohort. No differences in T-cell proliferation were observed between asymptomatic and symptomatic individuals. The results have implications for studies of HSV-2-specific CD4+ T-cell reactivity in general and for analysis of immunological differences between asymptomatic and symptomatic individuals in particular.

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T cell responses to synthetic peptides of herpes simplex virus type 1 glycoprotein D in naturally infected individuals

Archives of Virology ◽

10.1007/bf01319007 ◽

1993 ◽

Vol 130 (1-2) ◽

pp. 187-193 ◽

Cited By ~ 10

Author(s):

R. A. Damhof ◽

J. W. Drijfhout ◽

A. J. Scheffer ◽

J. B. Wilterdink ◽

G. W. Welling ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Synthetic Peptides ◽

Glycoprotein D ◽

Cell Responses ◽

Simplex Virus

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Diversity of the CD8+ T-Cell Response to Herpes Simplex Virus Type 2 Proteins among Persons with Genital Herpes

Journal of Virology ◽

10.1128/jvi.02659-05 ◽

2006 ◽

Vol 80 (11) ◽

pp. 5509-5515 ◽

Cited By ~ 79

Author(s):

Nancy Hosken ◽

Patrick McGowan ◽

Amalia Meier ◽

David M. Koelle ◽

Paul Sleath ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Cell Response ◽

T Cell Response ◽

Simplex Virus

ABSTRACT Cytolytic T cells play a major role in controlling herpes simplex virus type 2 (HSV-2) infections in humans. In an effort to more thoroughly evaluate the response to HSV-2 directly, ex vivo, we developed an enzyme-linked immunospot (ELISPOT) assay that utilized pools of overlapping synthetic peptides presented by autologous dendritic cells to purified CD8+ T cells. Donor response rates to individual open reading frames (ORFs) ranged from fewer than 5% responding to as many as 70% responding, with the greatest frequency of responses (by ORF) being directed against UL39, UL25, UL27, ICP0, UL46, and UL47 in descending order of frequency. HSV-2-seropositive subjects responded to as few as 3 or as many as 46 of the 48 ORFs tested, with a median of 11 ORFs recognized. HLA-B*07 expression correlated with stronger responses overall that were directed primarily against UL49 and UL46. Cumulative precursor frequencies in the blood ranged from 500 to almost 6,000 HSV-2 spot-forming units/106 CD8+ T cells. The magnitude and breadth of the response in the infected population were greater than previously appreciated. Whether this variability in the CD8+ T-cell response within individuals is associated with the frequency of viral reactivation warrants further study.

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T-cell-mediated mechanisms involved in resolution of genital herpes simplex virus type 2 (HSV-2) infection of mice

Journal of Reproductive Immunology ◽

10.1016/j.jri.2003.12.002 ◽

2004 ◽

Vol 61 (2) ◽

pp. 115-127 ◽

Cited By ~ 26

Author(s):

Gregg N. Milligan ◽

Kristen L. Dudley-McClain ◽

Christal G. Young ◽

Chin-Fun Chu

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Genital Herpes ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Simplex Virus

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Differential roles of B cells and IFN-γ-secreting CD4+ T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice

Journal of General Virology ◽

10.1099/0022-1317-82-4-845 ◽

2001 ◽

Vol 82 (4) ◽

pp. 845-853 ◽

Cited By ~ 98

Author(s):

Ali M. Harandi ◽

Bo Svennerholm ◽

Jan Holmgren ◽

Kristina Eriksson

Keyword(s):

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

B Cells ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Ifn Γ ◽

Simplex Virus

The role of B, CD4+ T and CD8+ T cells in both primary genital infection with attenuated herpes simplex virus type 2 (HSV-2) and development of protective immunity to a later challenge with virulent HSV-2 using lymphocyte-deficient mice has been elucidated. Following primary inoculation with attenuated thymidine kinase-deficient (TK−) HSV-2, B cell-deficient (μMT) mice developed a local viraemia and transient genital inflammation, suggesting a role for B cells in the innate control of local infection and inflammation. Natural antibodies are implicated in this process, as passive transfer of normal serum into μMT mice significantly reduced HSV-2 TK− shedding in the vaginal lumen, although it did not affect subsequent inflammation. Protection against lethal HSV-2 challenge was noted in HSV-2-vaccinated wild-type, CD8+ T cell-deficient and μMT mice and was characterized by strong virus-specific IFN-γ responses in vitro and delayed type hypersensitivity (DTH) responses in vivo. In contrast, CD4+ T cell-deficient (CD4−/−) mice had impaired HSV-2-specific IFN-γ production and DTH responses and succumbed rapidly to genital HSV-2 challenge. However, protective responses to HSV-2 could be induced in HSV-2-vaccinated CD4−/− mice by treatment with recombinant IFN-γ. Taken together, these results suggest that CD4+ T cells secreting IFN-γ are critical for immune protection against lethal genital HSV-2 re-infection, whereas B cells/natural antibodies have anti-viral and -inflammatory effects in the innate control of a primary infection.

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Pharmacological Inhibition of IRE-1 Alpha Activity in Herpes Simplex Virus Type 1 and Type 2-Infected Dendritic Cells Enhances T Cell Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.764861 ◽

2022 ◽

Vol 12 ◽

Author(s):

Eduardo I. Tognarelli ◽

Angello Retamal-Díaz ◽

Mónica A. Farías ◽

Luisa F. Duarte ◽

Tomás F. Palomino ◽

...

Keyword(s):

Dendritic Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

T Cell ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host’s antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1α). Here, we sought to evaluate if the activation of the IRE-1α pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1α in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4+ and CD8+ T cells. These findings suggest that the activation of the IRE-1α-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs.

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