Frequent and/or prolonged reactivation of herpes simplex virus (HSV) infection is common in human immunodeficiency virus (HIV) positive patients and causes greatly diminished quality of life due to disfiguring and painful skin, oral and genital lesions. Antiviral drug resistant HSV strains are on the rise especially in HIV patients; hence, new and improved treatment and preventive approaches are urgently needed. This project will identify immune mechanisms that may be harnessed to control HSV reactivation and acute disease in HIV/AIDS patients. Agents that enhance the immune system are promising as novel antiviral drugs as they: 1) may overcome immune suppression in HIV/AIDS patients, 2) may have long-term preventive properties, and 3) represent a greater challenge for the virus in terms of developing new resistance. Imiquimod and polyinosinic- polycytidylic (poly(I:C)) are two immune response modifies, which have successfully been used in humans and/or mice to treat acute HSV skin disease; however, their mechanisms of action are incompletely understood. Furthermore, their immune activating potency limits their prolonged use. Individual down-stream effectors of imiquimod and poly(I:C) activity, e.g., those studied here, may be better suited as therapeutic and preventive agents due to their more limited, yet focused, action. The IL-36 system involves three related cytokines, IL-36?, IL-36? and IL-36? and a common receptor, IL-36R. The system is predominantly expressed in epithelial tissues, such as the skin and oral and genital mucosa; tissues which are also the targets of HSV. The physiological function of the IL-36 system is unknown; however, preliminary, predominantly in vitro, studies suggest that it activates the immune system through leukocyte recruitment and initiation of the adaptive immune response. We were the first to demonstrate that poly(I:C), a double stranded RNA analogue often used to simulate viral infections, induces IL-36? expression and extracellular release. Recently we published our further work demonstrating that IL-36? is essential for the inflammatory immune response induced by imiquimod in the skin. Additional, unpublished data reveal that IL-36? deficient mice develop larger HSV-1 skin lesions and have a higher mortality rate than wild type mice. This leads us to hypothesize that the IL-36 system promotes immunity against HSV and the therapeutic effects of imiquimod and poly(I:C) is driven, at least in part, by the IL-36 system. Hence, in Aim 1 we will define the IL-36 dependent immune mechanisms directed against HSV.
In Aim 2 we will test our hypothesis that the IL-36 system is, at least in part, responsible for the therapeutic effects of imiquimod and poly(I:C). Finally, in Aim 3 we will test the therapeutic and preventive activity of IL-36. Correlations to human HSV disease and immune responses will be drawn and the impact of HIV infection examined. The knowledge gained may underpin the development of novel approaches to the management and control of not only HSV, but also other opportunistic and/or co-infections in HIV patients.
Infection with herpes simplex virus (HSV) increases the risk of contracting HIV. Co-infected HIV patients may suffer decreased quality of life as frequent and persistent reactivation of HSV is common. Drug resistant HSV infections are on the rise; hence, new and improved approaches to their control are needed. This project will explore host immune mechanisms that may be utilized as novel treatment approaches and strategies to prevent primary HSV infection. The latter may help reduce numbers of new HIV infections.
|Milora, Katelynn A; Uppalapati, Siva R; Sanmiguel, Julio C et al. (2017) Interleukin-36? provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses. Sci Rep 7:5799|
|Alvarez, Pilar; Jensen, Liselotte E (2016) Imiquimod Treatment Causes Systemic Disease in Mice Resembling Generalized Pustular Psoriasis in an IL-1 and IL-36 Dependent Manner. Mediators Inflamm 2016:6756138|