APO-HSV-2/HIV

Double infection by HSV-2 and HIV: how does HSV-2 infection facilitate for HIV infection?

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 Obiettivo del progetto (Objective)

'Globally, more than 40 million people are currently infected with HIV-1, with the vast majority of infections initiated at mucosal surfaces and approximately half of the world people now living with HIV are women. Herpes simplex type 2 (HSV-2) is one of the most common sexually transmitted viral diseases (STD) with an estimated prevalence of up to 50% among the female population worldwide giving rise to genital lesions and ulcers. Genital tract inflammation due to STD, such as HSV-2, increases expression of HIV receptors and co-receptors on all the resident target cells in genital mucosa. Apoptosis and apoptotic proteins, such as Fas have been showed to participate in homeostatic maintenance of vaginal epithelium. Considering the fact that disruption of the integrity of the vaginal mucosa resulting from HSV-2 heightens the risk of HIV transmission and may involve exacerbation of apoptosis mechanisms it is necessary to test how apoptosis during HSV-2 infection may add to disruption of vagina epithelium integrity and therefore, how it influences the outcome of double HIV-1/HSV-2 infection. To gain knowledge on this pathogenic scenario I will (i) identify the influence of HSV-2 on apoptosis and disruption of the vaginal mucosa using a mouse model of HSV-2 infection, (ii) examine the contribution of Fas and other receptors of the TNF family to vaginal epithelium lesions during HSV-2 infection (iii) analyze how HSV-2 infection can add to HIV-1 infection using double infection model of mice infected with HSV-2 and HIV-1/murine leukaemia A4070 pseudotype virus. Whenever applicable the relevance of the results obtained in the animal models will be verified in biopsy material from HSV-2 infected women. I expect that disclosure of the mechanisms responsible for increased susceptibility to HIV infection in HSV-2 infected women at the level of vaginal epithelial function will provide knowledge and opportunity to develop effective, affordable anti-HIV prophylactic therapy'

Introduzione (Teaser)

Herpes simplex type 2 infection is one of the most common sexually transmitted viral diseases, but it also makes one more prone to HIV transmission.

Descrizione progetto (Article)

Infection and inflammation of the genital tract by a sexually transmitted disease (STD) such as Herpes simplex virus type 2 (HSV-2) upset the mucosal layer of the vagina. Blisters or ulcers on the genitalia are the most frequently noticed symptoms. This vulnerable state increases the expression of human immunodeficiency virus (HIV) receptors and co-receptors on the surrounding cells affected by HSV-2.

The 'Double infection by HSV-2 and HIV: how does HSV-2 infection facilitate for HIV infection?' (APO-HSV-2/HIV) project set out to discover how programmed cell death (apoptosis) during HSV-2 infection contributes towards upsetting the delicate balances in the vaginal environment, and how this can influence the outcome of combined HIV-1/HSV-2 infection. Apoptosis is a necessary process for the regular renewal of vaginal epithelium or tissue. Fas, a regulatory protein that activates apoptosis, has been shown to play a role in maintaining vaginal epithelium.

The project aimed to determine if HSV-2 infection can lead to apoptosis and changes in vaginal mucosa, and how Fas and other receptors contribute to genital lesions during HSV-2 infection. Importantly, researchers wanted to examine how HSV-2 infection increases risk of HIV-1 infection.

Two mouse models were used. The in vitro model of HSV-2 epithelial infection showed a moderate level of apoptosis during infection, and the in vivo herpes genitalis model showed the presence of apoptotic HSV-2 infected and uninfected cells. In assessing the role of Fas in the development of lesions during HSV-2 infection, results showed that a Fas and Fas ligand (FasL) deficiency led to increased apoptosis and development of bigger vaginal lesions.

Project members concluded that HSV-2 infection leads to heightened processes of apoptosis and inflammation. However, Fas/FasL-induced apoptosis helps regulate the inflammatory response early on in HSV-2 infection and thus helps maintain the balance in vaginal mucosa. This is an important finding for the development of microbicides, topical antiviral agents that can protect against STDs.