HIV: THE AIDS VIRUS

HIV infection is via the foreskin

Over 25 million people have died from AIDS. To date 60 million have been infected with HIV (15,000 each day, i.e., one every 6 seconds; 4.3 million in 2003) and 40 million are currently living with HIV, leading to >15 million children being orphaned [www.unaids.org][105, 274]. By 2050 there could be one billion infected [142]! Half of HIV cases are men, most of whom have been infected through their penises [190], the foreskin having been implicated as early as 1986 [108]. Over 80% of these infections have arisen from vaginal intercourse [171].

How then does HIV enter a man's body in this way? Epidemiological data from more than 40 studies (discussed below) shows that HIV is much more common in uncircumcised, as opposed to circumcised, heterosexual men [111]. A wealth of evidence indicates that male circumcision protects against HIV infection, as acknowledged in the major journals Science [67, 68, 170] and Nature [380], and its promotion in HIV prevention is advocated [95].

During heterosexual intercourse the foreskin is pulled back down the shaft of the penis, meaning that the whole of its inner surface is exposed to vaginal secretions [345]. An early suggestion that attempted to explain the higher HIV infection in uncircumcised men was that the foreskin could physically trap HIV-infected vaginal secretions and provide a more hospitable environment for the infectious inoculum [57]. It was also suggested that the increased surface area, traumatic physical disruption during intercourse and inflammation of the glans penis (balanitis) could aid in recruitment of target cells for HIV-1. Initial thoughts were that the port of entry could potentially be the glans, sub-prepuce and/or urethra. It was suggested that in a circumcised penis the drier, more keratinized skin covering the penis may prevent entry. However, subsequent studies showed that the glans of the circumcised and uncircumcised penis were in fact identical in histological appearance, having exactly the same amount of protective keratin [345]. In contrast, the inner lining of the foreskin is a mucosal epithelium and lacks a protective keratin layer [28] (see picture below taken, with permission, from [28]). The foreskin's inner epithelium thus resembles histologically the lining of the nasal passages and vagina. All such mucosal epithelia are major targets for infection by micro-organisms (colds, flu, STIs, etc). Added to this is the fact that the uncircumcised penis is more susceptible to minor trauma and ulcerative disease, and the preputial sac could harbor pathogenic organisms in a pool of smegma [8]. The mucosal inner lining of the adult foreskin is rich in Langerhans cells and other immune-system cells (22.4, 11.5 and 2.4% of total cell population is represented by CD4+ T cells, Langerhans cells and macrophages) [267]. (This contrasts with the neonate, where the foreskin is deficient in such cells [376], the proportion being instead 4.9, 6.2 and 0.3%, respectively [267]). The respective percentages for immune-system cells in the cervical mucosa are: 6.2, 1.5 and 1.4% [267]. In the external layer of the foreskin, which is like the rest of the penis, the proportions are very much lower: 2.1, 1.3 and 0.7%, respectively [267]. Although the urethra is also a mucosal surface, Langerhans cells are rarer, and it is not regarded as a common site of HIV infection.

The counterintuitive observation that HIV risk is actually lower in circumcised men who have more frequent exposure than it is in circumcised men with less frequent exposure, has led to the hypothesis that repeated contact of the small area of exposed urethral mucosa with subinfectious inoculums may induce an immune response having a protective effect over and above that afforded by removal of the vulnerable foreskin [374]. The small area exposed may mean that the infectious inoculum per act of intercourse may be less likely to overwhelm the effects of partial protection as compared with the mucosal area exposed in a foreskin or vagina [374]. This hypothesis remains to be tested. Mucosal alloimmunization has also been suggested as a protective factor against HIV [271].


The immune cells of the inner lining of the foreskin help fight bacteria and viruses that accumulate under it. However, in the case of HIV, they act as a ‘Trojan horse', serving as portals for uptake of HIV into the body, where HIV entry generally requires CD4 receptors and cofactors such as chemokine receptors CCR5 and CXCR4 present in high density on the surface of Langerhans cells [8]. Moreover, the selective entry of HIV via the inner foreskin has been shown by direct experimentation [28, 38, 267]. Punch biopsies were taken from fresh foreskin obtained immediately after circumcision of the adult male. Cultures were made of cells from the external surface (which resembles the rest of the penis) and from the inner mucosal surface of the foreskin. Live HIV tagged with a fluorescent marker was then applied. Within minutes the HIV entered the Langerhans cells [see picture above - obtained, with permission, from [28] (similar images can be seen in [267]). No uptake occurred for cultured epithelium of the keratinized outer surface of the foreskin, i.e., the part that resembles the skin of the circumcised penis. The mean number of HIV copies per 1000 cells (determined by quantitative PCR) one day after infection was 301 for the mucosal inner foreskin, but was undetectable in the outer, external, foreskin [267]. For cervical biopsies mean HIV copy number was 30, showing that the mucosal inner foreskin is 10-times more susceptible to HIV infection than the cervix [267]. The HIV receptor CCR5 was, moreover especially prevalent on foreskin tissue cells [267]. This biological work thus nicely confirms the epidemiological evidence to be discussed below. It is furthermore supported by experiments in which SIV (the monkey equivalent of HIV) has been applied to foreskin of monkeys, that then became infected [232]. The monkey work also showed infected Langerhans cells. Antigen presenting cells in the mucosa of the inner foreskin [164] are a primary target for HIV infection in men [345].



The foreskin is thus the weak point that allows HIV to infect men during heterosexual intercourse with an infected partner. A circumcised man with a HEALTHY penis is thus very unlikely to get infected. However, ulcerations (from herpes, syphilis, etc) or abrasions on the penis will allow infection and a circumcised man with these will continue to be at risk of HIV, as well as some other STIs. Individuals with HSV-2 have twice the risk of acquiring HIV than those without, and those infected with both viruses are more likely to transmit HIV than if they just have HIV [341]. Giving co-infected patients acyclovir has therefore been suggested. Of course condom use is strongly advocated in attempting to lower transmission. Condoms, when ALWAYS used, reduce HIV infection by 80–90% [146]. Condom use remains low, however [105]. Moreover, condoms are not a panacea, and a man with a foreskin can still be infected by HIV-laden fluids coming into contact with the inner foreskin, for example during foreplay, prior to application of the condom preceding vaginal penetration. A condom can, moreover, break!
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