Keratinization: A Biologic Alternative to Male Circumcision in the Prevention of HIV Infection?

August 1, 2008

In recent years, few breakthroughs in HIV prevention science have been realized. Preexposure prophylaxis (PrEP), involving the use of antiretrovirals just before a potentially risky sexual encounter, is an intriguing concept, although it’s not new.

In recent years, few breakthroughs in HIV prevention science have been realized. Preexposure prophylaxis (PrEP), involving the use of antiretrovirals just before a potentially risky sexual encounter, is an intriguing concept, although it’s not new. In 2005, the CDC reported that 7% of uninfected men who have sex with men (MSM) had taken an antiretroviral agent before engaging in a high-risk behavior.1 But the efficacy of this strategy is unclear, despite large-scale clinical trials,2 and complete protection in animal models has been shown to require high daily doses of at least 2 antiretrovirals, typically tenofovir and emtricitabine.3 In addition, PrEP accelerated transmitted drug resistance among monkeys with breakthrough infections.3 Against this background, male circumcision appears to hold much promise, at least for some vulnerable populations. Recently, a potential chemical means of mimicking its efficacy has been proposed. But first, I’ll review some clinical data.

Three randomized, controlled trials conducted in Africa found that adult male circumcision decreased the incidence of HIV acquisition by men via penile-vaginal intercourse by 48% to 60% over a mean follow-up of 18 months.4-6 A retrospective study of Ugandan couples showed that circumcised men also were 30% less likely to transmit HIV to their female partners.6 These results for prevention of female-to-male transmission of HIV were equivalent to protection rates afforded by some widely used bacterial and viral vaccines.
Although concerns have been raised about “risk compensation” or engendering feelings of invulnerability to HIV infection following this procedure, during the first year post circumcision, men did not engage in more risky sexual behaviors than their uncircumcised counterparts, at least in a Kenyan cohort.7 In addition, when a man is circumcised, there is a decreased risk of transmitting other sexually transmitted infections (STIs), which may facilitate the spread of HIV, including Chlamydia and Trichomonas8 infections and possibly human papillomavirus infection,9 which is linked to cervical and oral cancers. These data argued strongly for swift implementation of this approach in highly vulnerable populations.

However, the applicability of those studies among male heterosexuals to MSM populations is unclear. A recent respondent-driven sampling of 1154 black and 1091 Latino MSM from 3 major US cities found that circumcision status was not associated with prevalent HIV infection, nor did it correlate with a reduced likelihood of HIV infection among men who had engaged in unprotected insertive and not unprotected receptive anal intercourse.10 In addition, surgical complications occur in 1% to 7% of cases under the best of circumstances.11 The likelihood of facilitating HIV infection when a circumcised person fails to restrain from sexual intercourse for 4 to 6 weeks after the procedure is another confounding factor.12 Which brings us back to a new biologic approach in which the male foreskin still has a prominent role.

The external foreskin and shaft of the penis are keratinized and not susceptible to HIV infection.13 In contrast, the inner foreskin and frenulum have a keratin layer about half the thickness of the penile shaft.14 Their surfaces contain cells-Langerhans cells, dendritic cells, CD4+ T cells, and macrophages-that are highly susceptible to HIV infection and more abundant in men with a history of STIs.13 This raises an intriguing question: could the keratinization of these susceptible tissues be enhanced as a form of chemical circumcision that might be equally protective against HIV and not prone to the procedure-based risks described above?

Human and non-human primate studies have shown that the rate of HIV and simian immunodeficiency virus (SIV) vaginal transmission is decreased when systemic estrogen dominates over progesterones.15 Systemic estrogen protects against SIV vaginal transmission,15 while progesterone implants enhance it.16 In a study of macaque monkeys with low estrogen levels (secondary to bilateral oophorectomy), 4 weeks of twice-weekly intravaginal application of a commercially available estriol cream (Ovestin; Oestriol), which is used to treat atrophic vaginitis in women, led to keratinization (“cornification”) of the vagina.15 This protected treated animals against intra-vaginal challenge with SIV, with an 8.3% infection rate versus 75.0% for animals receiving a placebo gel.15 Protection occurred in the absence of a measurable increase in circulating levels of estrogen. Treated animals were not protected against direct injection of SIV beneath the vaginal surface.

Taking a clue from these studies, Drs Andre Pask and Roger Short of the University of Melbourne and colleagues17 applied estriol cream to the inner foreskin of 2 men. The epithelium underwent keratinization within 24 hours and the positive response-up to a 4-fold increase in keratin production-persisted for at least 5 days.

Studies are now being contemplated to see whether such a change can protect the underlying Langerhans cells from contact with HIV virions.17 Presumably, this research would need to be carried out in monkeys first, but the study proponents are enthusiastic about its clinical relevance. Keratin creates a “natural condom,” stated Short during a recent interview with the 2 investigators, “a biological membrane which [HIV] can’t get through.”18 Pask added that by “using keratin, we can increase the body’s natural defense. . . . It’s not a contraception . . . but it is a living condom and a perfect protection against HIV.”18

Use of a locally applied agent, under the susceptible partner’s control, to enhance foreskin keratinization is certainly an intriguing concept. Implementation of male circumcision, particularly in such countries as India, China, and much of Southeast Asia where it may be culturally unacceptable, is a costly and daunting task. For example, although it is cost-effective, rapid scale-up of adult male circumcision poses a great fiscal stress in many sub-Saharan countries.19 And a recent Indian government study to gauge the acceptance of this procedure triggered a massive backlash by Hindu fundamentalists, who called it “obnoxious” and a “conspiracy.”20 Nevertheless, if topical estrogen-inexpensive, available, a natural product, easy to apply-works, it might be an adjunct or alternative to circumcision. Estrogen cream could also be used as a condom lubricant to protect both partners.17 Whether this is a “perfect protection” remains to be seen.

Although clinical trials in Africa are planned by the Melbourne investigators,18 key questions remain. For example, there may be alternatives or adjuncts to estrogen for men in terms of facilitating keratinization. Many hormones and natural products, such as vitamin D3, retinoic acid, progesterone, and thyroid hormone, suppress this process.21 What products are available to enhance it? In addition, genital epithelial cells, which are not infectable by HIV, can nonetheless capture HIV on their surfaces and maintain it in a fully infectious state for 6 days or more, at least in vitro, permitting transmission to any CD4+ T cell or macrophage that might come along.22 Could increasing the keratin layer of the foreskin amplify this viral “trap” and thereby enhance, not block, HIV transmission?
We look forward to further research in this area.


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