Studies of Initial innate immune responses to Herpes Simplex Virus in human skin guide vaccine development.

Summary

To join an experienced team of researchers in the Westmead Millennium Institute to study the human immunology of Herpes Simplex Virus (HSV) to facilitate vaccine development. Such a vaccine would have impact on the spread of both HSV and HIV.

Supervisor(s)

Professor Tony Cunningham, Dr Min Kim

Research Location

Westmead - Westmead Institute for Medical Research

Program Type

PHD

Synopsis

Herpes Simplex Viruses type 1 and 2 (HSV) can cause cold sores, genital herpes, keratitis/blindness, encephalitis and neonatal herpes. 70-80% of the Australian population is infected with HSV-1 and 12% with HSV-2. Once it infects the human body, it persists throughout life. HSV-2 infection increases the acquisition of HIV by 2-3 fold. Current vaccine candidates are inadequate and need boosted and immunogenicity through better knowledge of the initial immune response.

Understanding the interaction between HSV infection of genital skin/mucosa and its interactions with skin dendritic cells (DCs) is of key importance in elucidating how HSV specific CD4 and CD8 T lymphocytes are activated and home to the infected lesion and persist at the site of infection between lesions to eradicate infection.

It is now known that the interaction between various classes of DCs in the skin is required for this process. Initially it was thought that HSV infection of Langerhans cells led to migration of these cells to lymph node and to stimulation of CD4 and CD8 lymphocyte responses there. One of these dermal DC subsets (BDCA3+ DCs) can stimulate the key CD8 T lymphocyte response. We have now shown that HSV infects human Langerhans cells in the epidermis which results in transfer to dermal DCs which exit from the dermis and then travel to lymph node. We have developed a unique model of HSV infected human foreskins which shows the direct interaction between HSV infected epidermal LCs and dermal DCs.

This study will give insight on fundamental understanding of how innate and adaptive immune cells in skin epidermis and dermis cooperate to eliminate HSV and will contribute to improvement of HSV vaccine candidates.

Research Plan
1.Examine migration of infected Langerhans cells out of epidermis and through basement membrane by real time fluorescence
2.Examine which molecules or cytokines/chemokines are involved in the interaction of HSV infected LCs with dermal DCs prior to viral transfer
3.Examine effects of specific chemokines such as IL8 on HSV induced immigration of BDCA3+ dermal DCs from venules into dermis
4.Examine whether BDCA3+ DCs can indeed stimulate HSV specific CD8 T lymphocytes, ‘the missing link in HSV vaccine development'

Additional Information

Our lab has been continuously funded by NHMRC for studies of the human immunology of HSV to facilitate vaccine development since 1985. Our studies determined the composition of the partly successful GSK Simplirix vaccine candidate which stimulates CD4 T lymphocytes and neutralizing antibody but not CD8 T lymphocytes. We will provide a stipend of 28,800 p.a. up to 3 years.

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Keywords

herpes simplex virus, Langerhans cells, dermal dendritic cells, BDCA3+ dendritic cells, human skin, virus to cell interaction, cell to cell interaction, Cytokine, chemokine

Opportunity ID

The opportunity ID for this research opportunity is: 1923

Other opportunities with Professor Tony Cunningham

Other opportunities with Dr Min Kim