Glycoprotein-D–Adjuvant Vaccine to Prevent Genital Herpes

Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

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“…Virus-mediated downmodulation of CD40 and CD54 may favour viral spread, which is mainly controlled by Th1 cytokine-induced T cells [65,66].…”

Section: Subsets In Innate and Adaptive Immunity To Hsvmentioning

confidence: 99%

Langerhans cells and viral immunity

2008

Self Cite

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“…Although these vaccines are safer than live attenuated vaccines, they may not be capable of generating a robust and durable immune response and the high doses of virus required might make them difficult to manufacture. Subunit vaccines should be safer than either of these strategies but have met with mixed results in human clinical trials [6,23]. These vaccines typically generate neutralizing antibody titers, but this alone is likely insufficient to confer a high degree of protection [6].…”

Section: Discussionmentioning

confidence: 99%

“…While the subunit vaccine regimens proved to be immunogenic and generated high-titered neutralizing antibodies, a clinical trial using this approach vaccine was unable to demonstrate protection against acquisition ofHSV-2 infection suggesting that a neutralizing antibody response is insufficient to prevent infection with this virus [6]. Recent results with an engineered subunit vaccine and novel adjuvant has met with some success in clinical trials and appeared to be protective against clinically apparent disease in seronegative women, but appeared to be ineffective in men [23].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of AD472, a live attenuated recombinant herpes simplex virus type 2 vaccine in guinea pigs

Prichard¹,

Kaiwar²,

Jackman³

et al. 2005

Vaccine

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An attenuated recombinant herpes simplex virus type 2 (HSV-2), designated as AD472, was constructed by deleting both copies of the γ 1 34.5 gene, UL55-56, UL43.5, and the US10-12 region from HSV-2 strain G. This virus was engineered to be a safe and effective live attenuated HSV-2 vaccine and was tested in the guinea pig model of genital herpes to evaluate its ability to protect from disease upon challenge with the wild type (wt) virus, HSV-2 (G). AD472 administered intramuscularly did not prevent infection or virus replication in the vaginal tract, but did reduce both lesion development and severity in a dose-dependent manner in guinea pigs challenged with the wt virus. Frequency of reactivation from latency was low compared with that of the parent virus, HSV-2 (G). Immunization with AD472 at doses of 1 × 10 5 PFU generally precluded colonization of the ganglia or establishment of latency by the challenge virus. Results presented here support the concept of a rationally engineered live attenuated vaccine for the prevention of the genital disease associated with infection by HSV-2.

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“…However, women who were seronegative for HSV-1 and 2 mounted strong anti-HSV-2 immune responses. 106 With genital tract Chlamydia infection rates on the continual rise and the asymptomatic nature of infections, these are important aspects that have yet to be examined in any way.…”

Section: Problems With Vaccine Developmentmentioning

confidence: 99%

REVIEW ARTICLE: Chlamydia trachomatis, a Hidden Epidemic: Effects on Female Reproduction and Options for Treatment

Carey

Beagley

2010

American J Rep Immunol

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Citation Carey AJ, Beagley KW. Chlamydia trachomatis, a hidden epidemic: effects on the female reproduction and options for treatment. Am J Reprod Immunol 2010The number of genital tract Chlamydia trachomatis infections is steadily increasing worldwide, with approximately 50–70% of infections asymptomatic. There is currently no uniform screening practice, current antibiotic treatment has failed to prevent the increased incidence, and there is no vaccine available. We examined studies on the epidemiology of C. trachomatis infections, the effects infections have on the female reproductive tract and subsequent reproductive health and what measures are being taken to reduce these problems. Undetected or multiple infections in women can lead to the development of severe reproductive sequelae, including pelvic inflammatory disease and tubal infertility. There are two possible paradigms of chlamydial pathogenesis, the cellular and immunological paradigms. While many vaccine candidates are being extensively tested in animal models, they are still years from clinical trials. With no vaccine available and antibiotic treatment unable to halt the increased incidence, infection rates will continue to increase and cause a significant burden on health care systems.

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Glycoprotein-D–Adjuvant Vaccine to Prevent Genital Herpes

Cited by 724 publications

References 26 publications

Langerhans cells and viral immunity

Langerhans cells and viral immunity

Evaluation of AD472, a live attenuated recombinant herpes simplex virus type 2 vaccine in guinea pigs

REVIEW ARTICLE: Chlamydia trachomatis, a Hidden Epidemic: Effects on Female Reproduction and Options for Treatment

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