Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8<sup>+</sup>cytotoxic T lymphocyte responses

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Herpes simplex virus (HSV) establishes a lifelong infection in humans. Reactivation of latent virus occurs intermittently so that the immune system is frequently exposed to viral Ag, providing an opportunity to evaluate memory T cells to a persistent human pathogen. We studied the persistence of genital herpes lesion-derived HSV-specific CD8+ CTL from three immunocompetent individuals with frequently recurring genital HSV-2 infection. All CTL clones were HSV-2 type specific and only one to three unique clonotypes were identified from any single biopsy specimen. The TCRBV genes utilized by these clonotypes were sequenced, and clonotype-specific probes were used to longitudinally track these clonotypes in PBMC and genital lesions. CTL clonotypes were consistently detected in PBMC and lesions for at least 2 and up to 7 years, and identical clonotypes infiltrated herpes lesions spaced as long as 7.5 years apart. Moreover, these clones were functionally lytic in vivo over these time periods. Additionally, CTL clones killed target cells infected with autologous viral isolates obtained 6.5 years after CTL clones were established, suggesting that selective pressure by these CTL did not result in the mutation of CTL epitopes. Thus, HSV recurs in the face of persistent CD8+ CTL with no evidence of clonal exhaustion or mutation of CTL epitopes as mechanisms of viral persistence.

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 98%

Long Term Persistence of Herpes Simplex Virus-Specific CD8+ CTL in Persons with Frequently Recurring Genital Herpes

Posavad

Huang²,

Barcy³

et al. 2000

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“…Wells were scored as positive if the cpm from the sample wells were greater than 3ϫ SD above the mean cpm from the control wells. The ppfs were calculated by a standard method (19).…”

Section: Lymphoproliferation Assaymentioning

confidence: 99%

γδ T Cell-Deficient Mice Have a Down-Regulated CD8+ T Cell Immune Response AgainstEncephalitozoon cuniculiInfection

Moretto

Durell

Schwartzman³

et al. 2001

γδ T cells have been reported to play an essential effector role during the early immune response against a wide variety of infectious agents. Recent studies have suggested that the γδ T cell subtype may also be important for the induction of adaptive immune response against certain microbial pathogens. In the present study, an early increase of γδ T cells during murine infection with Encephalitozoon cuniculi, an intracellular parasite, was observed. The role of γδ T cells against E. cuniculi infection was further evaluated by using gene-knockout mice. Mice lacking γδ T cells were susceptible to E. cuniculi infection at high challenge doses. The reduced resistance of δ−/− mice was attributed to a down-regulated CD8+ immune response. Compared with parental wild-type animals, suboptimal Ag-specific CD8+ T cell immunity against E. cuniculi infection was noted in δ−/− mice. The splenocytes from infected knockout mice exhibited a lower frequency of Ag-specific CD8+ T cells. Moreover, adoptive transfer of immune TCRαβ+ CD8+ T cells from the δ−/− mice failed to protect naive CD8−/− mice against a lethal E. cuniculi challenge. Our studies suggest that γδ T cells, due to their ability to produce cytokines, are important for the optimal priming of CD8+ T cell immunity against E. cuniculi infection. This is the first evidence of a parasitic infection in which down-regulation of CD8+ T cell immune response in the absence of γδ T cells has been demonstrated.

“…The infection is controlled by local innate and adaptive immunity including neutrophils (16) and CTLs (17)(18)(19)(20). In one study surveying HIV ϩ to HIV Ϫ patients, the frequency of recurrence of HSV-2 to the prevalence of precursor CTLs was highly correlated (21). Other effector cells (e.g., NK cells) and cytokines such as IFN-␥ have been suggested to control HSV-2 infection in the vagina (22).…”

mentioning

confidence: 99%

The Application of a Plasmid DNA Encoding IFN-α1 Postinfection Enhances Cumulative Survival of Herpes Simplex Virus Type 2 Vaginally Infected Mice

Härle

Noisakran

Carr

2001

Using a hormonally induced susceptibility mouse model to investigate vaginal HSV type 2 (HSV-2) infection, a study was undertaken to determine the efficacy of a plasmid DNA encoding IFN-α1 introduced into the vaginal lumen postinfection (PI). Mice infected with HSV-2 intravaginally and treated intravaginally 24 h later with 100 μg DNA encoding IFN-α1 showed enhanced survival (10/15) in comparison to mice treated with 100 μg plasmid DNA vector alone (3/10) or vehicle (4/27). In contrast, mice receiving recombinant IFN-αA (5–500 U/vagina) 24 h PI showed no significant survival in comparison to the vehicle (saline)-treated group. The protective effect was time dependent in that mice receiving the IFN-α1 transgene 48 h PI succumbed at a rate similar to the plasmid DNA vector-treated group. The increase in cumulative survival elicited by the transgene corresponded with a reduction in viral replication and Ag expressed in the vaginal epithelium early (i.e., 3 days PI) during acute infection and replicating virus recovered in the spinal cord day 7 PI. By day 7 PI, HSV-2 glycoprotein B transcript expression was no longer detectable in vaginal tissue from the IFN-α1 transgene-treated group (0/8) compared with levels expressed in plasmid vector-treated controls (4/6 mice surveyed were positive). Collectively, these results suggest the application of DNA encoding type I IFN is an effective and alternative approach to currently prescribed therapies in controlling vaginal HSV-2 infection by antagonizing viral replication.