Association of Major Histocompatibility Complex Determinants with the Development of Symptomatic and Asymptomatic Genital Herpes Simplex Virus Type 2 Infections

Lekstrom-Himes, Julie; Hohman, Patricia; Warren, Terri; Wald, Anna; Nam, Jun Mo; Simonis, Toni B.; Corey, Lawrence; Straus, Stephen E.

doi:10.1086/314729

Cited by 52 publications

(52 citation statements)

References 55 publications

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“…Based on the fact that HSV-1 enters, replicates, spreads, and establishes latent infections with virtually identical efficiencies in C57BL/6 and BALB/c mice, individuals of the species Mus musculus do not appear to differ fundamentally in their innate resistance to HSV-1 infection. Likewise, although it has been implied that differences in host resistance are relevant in explaining what differentiates humans with recurrent herpetic disease from the vast majority of asymptomatic carriers of HSV-1 and HSV-2 (15,29,31,33), there is little epidemiological evidence to support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

Halford

Balliet

Gebhardt

2004

J Virol

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It is often stated that individuals of a species can differ significantly in their innate resistance to infection with herpes simplex virus type 1 (HSV-1). Three decades ago Lopez reported that C57BL/6 mice could survive a 5,000-fold-higher inoculum of HSV-1 given intraperitoneally than mice of the A or BALB/c strain (Nature 258:152-153, 1975). Susceptible strains of mice died of encephalitis-like symptoms, suggesting that viral spread to the central nervous system was the cause of death. Although Lopez's study documented that C57BL/6 mice were resistant to the development of HSV-1 encephalitis and mortality, the resistance of C57BL/6 mice to other steps of the HSV-1 infection process was not assessed. The results of the present study extend these observations to clarify the difference between resistance to (i) HSV-1 pathogenesis, (ii) HSV-1 replication, (iii) HSV-1 spread, and (iv) the establishment of latent HSV-1 infection. Although C57BL/6 mice are more resistant to HSV-1 pathogenesis than BALB/c mice, the results of the present study establish that HSV-1 enters, replicates, spreads, and establishes latent infections with virtually identical efficiencies in C57BL/6 and BALB/c mice. These observations raise questions about the validity of the inference that differences in natural resistance are relevant in explaining what differentiates humans with recurrent herpetic disease from the vast majority of asymptomatic carriers of HSV-1 and HSV-2.

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Section: Discussionmentioning

confidence: 99%

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

Halford

Balliet

Gebhardt

2004

J Virol

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“…One genetic mechanism may be immunologic determinants of disease severity that are associated with HLA expression. A prospective study of 146 subjects has identified several HLA alleles that are associated with HSV-2 infection or with frequent symptomatic genital recurrences (40). Most significantly, the presence of HLA-B8 and the absence of HLA-B27 and -Cw2 were associated with symptomatic disease in HSV-2-infected subjects, and HLA-Cw4 was significantly associated with HSV-2 infection (40).…”

Section: Discussionmentioning

confidence: 99%

T Cell Immunity to Herpes Simplex Viruses in Seronegative Subjects: Silent Infection or Acquired Immunity?

Posavad

Wald

Hosken³

et al. 2003

The Journal of Immunology

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During the course of investigating T cell responses to HSV among volunteers entering trials of investigational genital herpes vaccines, 6 of the 24 immunocompetent subjects with no prior history of oral/labial or genital herpes possessed HSV-specific T cell immunity but, by multiple determinants of even the most sensitive serological assays, remained seronegative to HSV-1 and -2. Of these six immune seronegative (IS; HSV-seronegative with HSV-specific T cell responses) subjects, two had transient HSV-specific T cell responses, while four had CD4+ and CD8+ T cell responses directed at HSV that persisted for up to 4 years. CD4+ T cell clones were isolated that recognized and had high binding affinities to epitopes in HSV-2 tegument proteins. All six IS subjects had potential sexual exposure to an HSV-2-infected sexual partner. Oral and genital mucosal secretions were sampled and tested for the presence of infectious HSV and HSV DNA. No evidence of HSV was detected in >1500 samples obtained from these IS subjects. The identification of persistent T cell responses to HSV in seronegative subjects is a novel finding in the herpesvirus field and suggests either undetected infection or acquired immunity in the absence of infection. Understanding the basis of these acquired immune responses may be critical in developing effective vaccines for genital herpes.

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“…Early in the development of recurrent lesions, HSV-1-specific IFN-␥-producing CD4 ϩ T cells that display a cytotoxic activity predominate in the mononuclear infiltrate surrounding HSV-1-infected epidermal cells, which strongly express HLA-DR (47). For many years, the association of HLA-DR haplotypes with susceptibility to both labial and genital herpes has been appreciated (27,41,44,55). Among the HLA-DR alleles, DRB1*04, DRB1*07, DRB1*11, and DRB1*13 are most frequent in the populations studied (26,35,41,55).…”

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confidence: 99%

“…For many years, the association of HLA-DR haplotypes with susceptibility to both labial and genital herpes has been appreciated (27,41,44,55). Among the HLA-DR alleles, DRB1*04, DRB1*07, DRB1*11, and DRB1*13 are most frequent in the populations studied (26,35,41,55). DRB1*13 is frequently seen in symptomatic HSV infection, while DRB1*04 is most frequent in individuals with asymptomatic HSV infection (41).…”

mentioning

confidence: 99%

Asymptomatic Human CD4⁺Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B

Chentoufi

Binder

Berka

et al. 2008

J Virol

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The identification of "asymptomatic" (i.e., protective) epitopes recognized by T cells from herpes simplex virus (HSV)-seropositive healthy individuals is a prerequisite for an effective vaccine. Using the PepScan epitope mapping strategy, a library of 179 potential peptide epitopes (15-mers overlapping by 10 amino acids) was identified from HSV type 1 (HSV-1) glycoprotein B (gB), an antigen that induces protective immunity in both animal models and humans. Eighteen groups (G1 to G18) of 10 adjacent peptides each were first screened for T-cell antigenicity in 38 HSV-1-seropositive but HSV-2-seronegative individuals. Individual peptides within the two immunodominant groups (i.e., G4 and G14) were further screened with T cells from HLA-DRgenotyped and clinically defined symptomatic (n ‫؍‬ 10) and asymptomatic (n ‫؍‬ 10) HSV-1-seropositive healthy individuals. Peptides gB [161][162][163][164][165][166][167][168][169][170][171][172][173][174][175] ؉ T cells from symptomatic patients preferentially recognized gB 661-675 (P < 0.0001). Thus, we identified three previously unrecognized CD4؉ CTL peptide epitopes in HSV-1 gB. Among these, gB 166-180 and gB 666-680 appear to be "asymptomatic" peptide epitopes and therefore should be considered in the design of future herpes vaccines.Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are ubiquitous viruses that infect a majority of people worldwide (3,22,68). Shedding of reactivated HSV is estimated to occur at rates of 3 to 28% in adults who harbor latent HSV in their sensory neurons (32,(66)(67)(68). However, the vast majority of these individuals do not experience recurrent herpetic disease and are designated "asymptomatic patients" (22,40,68). In contrast, in some individuals (symptomatic patients), reactivation of latent virus leads to induction of "pathogenic" HSVspecific CD4 ϩ and CD8 ϩ T cells (22, 68) and recurrent disease, ranging from rare episodes occurring every 5 to 10 years to outbreaks occurring monthly or even more frequently among a small proportion of subjects (22,26,60). Interestingly, for genital herpes, symptomatic and asymptomatic patients have similar virus shedding rates (68). It is likely that the same is true for ocular and oro-facial herpes, since shedding rates in tears and saliva of asymptomatic individuals have been reported to be as high as 33.5% (22,29,40,42). Latently infected patients are at risk of developing severe immunopathology, such as blinding herpetic stromal keratitis (HSK) (primarily due to HSV-1), painful genital ulcerations (primarily due to HSV-2), and in rare cases, fatal HSV encephalitis (reviewed in reference 72).Considering the wealth of data addressing the role of T cells in animal models, it is surprising how few reports explore the immunologic basis of symptomatic and asymptomatic HSV infections in humans. The HSV-1-specific CD4 ϩ T-cell responses in the cornea are much more likely to cause pathology than those in the genital tract or anus/buttocks region. Indeed, the involvement of CD4 ϩ T cells that produce Th1 cyt...

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Association of Major Histocompatibility Complex Determinants with the Development of Symptomatic and Asymptomatic Genital Herpes Simplex Virus Type 2 Infections

Cited by 52 publications

References 55 publications

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

T Cell Immunity to Herpes Simplex Viruses in Seronegative Subjects: Silent Infection or Acquired Immunity?

Asymptomatic Human CD4⁺Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B

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Association of Major Histocompatibility Complex Determinants with the Development of Symptomatic and Asymptomatic Genital Herpes Simplex Virus Type 2 Infections

Cited by 52 publications

References 55 publications

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

T Cell Immunity to Herpes Simplex Viruses in Seronegative Subjects: Silent Infection or Acquired Immunity?

Asymptomatic Human CD4+Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B

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Product

Resources

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Asymptomatic Human CD4⁺Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B