In 2006, 39.5 million people were currently infected with HIV, and there were 4.3 million new infections, making HIV one of the greatest health crises in human history. There is a desperate need to develop new methods to prevent HIV infection. The results of three large randomised trials of male circumcision, carried out in South Africa [1], Kenya [2] and Uganda [3], leave no doubt that circumcision more than halves a man’s risk of HIV infection [4,5], and the protective effect is thought to be due to the physical removal of most of the inner foreskin epithelium. This epithelium is richly supplied with Langerhans cells, the main site of HIV entry into the penis [6]. However, Langerhans cells are also a vital part of the body's natural epithelial defence against HIV infection, since they contain the c-type lectin Langerin that normally degrades any virions entering the cell [7,8]. When large amounts of virus are present, the Langerin reserves may be depleted, so that the Langerhans cells instead become vectors for transporting virus to the regional lymph nodes, establishing a systemic infection.
Langerhans cells are also the primary site of HIV entry into the female reproductive tract [9]. It has long been known that the human vaginal epithelium responds to topical oestrogen administration by thickening and keratinization, and vaginal oestrogen cream or tablets are widely used by postmenopausal women to treat vaginal atrophy [10,11]. The vaginal epithelial structure has a direct effect on its susceptibility to HIV infection. A decline in oestrogen levels in women after the menopause is associated with a four to eightfold increased risk of contracting HIV [12].
To determine how oestrogen affects the susceptibility of the vaginal epithelium to HIV infection, ovariectomised Rhesus monkeys were treated with either intravaginal oestriol or base cream and then challenged intravaginally with Simian Immunodeficiency Virus (SIV) [13]. Oestriol treated animals showed a dramatically increased resistance to SIV infection; only one of the twelve oestriol treated animals became infected when challenged with SIV, compared to six of the eight ovariectomised controls (p=0·0044) [13]. The treated animals did become infected if the SIV was injected beneath the vaginal epithelium, showing that the resistance to infection was occurring at the epithelial surface. The increased keratinization of the vaginal epithelium induced by the topical oestriol treatment apparently helped to reduce the number of SIV virions from coming into contact with the Langerhans cells, thus preventing infection.
The inner foreskin is a mucosal epithelium similar to that of the postmenopausal vagina, with a very thin layer of overlying keratin giving little protection to the underling Langerhans cells [6]. We have examined the ability of topical oestrogen to increase keratin production by the inner foreskin epithelium. By thickening the overlying protective layer of keratin, it may be possible to reduce the viral load to which the Langerhans cells are exposed, thus increasing resistance to HIV infection.
Download
PDF Ebook Topical Oestrogen Keratinises The Human Foreskin and May Help Prevent HIV Infection
