Male Circumcision and HIV Prevention: Looking to the Future

Now that male circumcision has been shown to have a protective effect for men against HIV infection when engaging in vaginal intercourse with HIV-infected women, the research focus needs to shift towards the operational studies that can pave the way for effective implementation of circumcision programs. Behavioral research is needed to find out how people perceive the procedure and the barriers to and facilitators of uptake. It should also assess the risk of an increase in unsafe sex after circumcision. Social research must examine cultural perceptions of the practice, in Africa and beyond, including how likely uncircumcised communities are to access surgery and what messages are needed to persuade them. Advocates of male circumcision would benefit from research on how to influence health policy-makers, how best to communicate the benefits to the public, and how to design effective delivery models

Topical Oestrogen Keratinises The Human Foreskin and May Help Prevent HIV Infection

With the growing incidence of HIV, there is a desperate need to develop simple, cheap and effective new ways of preventing HIV infection. Male circumcision reduces the risk of infection by about 60%, probably because of the removal of the Langerhans cells which are abundant in the inner foreskin and are the primary route by which HIV enters the penis. Langerhans cells form a vital part of the body's natural defence against HIV and only cause infection when they are exposed to high levels of HIV virions. Rather than removing this natural defence mechanism by circumcision, it may be better to enhance it by thickening the layer of keratin overlying the Langerhans cells, thereby reducing the viral load to which they are exposed. We have investigated the ability of topically administered oestrogen to induce keratinization of the epithelium of the inner foreskin. Histochemically, the whole of the foreskin is richly supplied with oestrogen receptors. The epithelium of the inner foreskin, like the vagina, responds within 24 hours to the topical administration of oestriol by keratinization, and the response persists for at least 5 days after the cessation of the treatment. Oestriol, a cheap, readily available natural oestrogen metabolite, rapidly keratinizes the inner foreskin, the site of HIV entry into the penis. This thickening of the overlying protective layer of keratin should reduce the exposure of the underlying Langerhans cells to HIV virions. This simple treatment could become an adjunct or alternative to surgical circumcision for reducing the incidence of HIV infection in men

Risk Compensation Is Not Associated with Male Circumcision in Kisumu, Kenya: A Multi-Faceted Assessment of Men Enrolled in a Randomized Controlled Trial

Three randomized controlled trials (RCTs) have confirmed that male circumcision (MC) significantly reduces acquisition of HIV-1 infection among men. The objective of this study was to perform a comprehensive, prospective evaluation of risk compensation, comparing circumcised versus uncircumcised controls in a sample of RCT participants.Between March 2004 and September 2005, we systematically recruited men enrolled in a RCT of MC in Kenya. Detailed sexual histories were taken using a modified Timeline Followback approach at baseline, 6, and 12 months. Participants provided permission to obtain circumcision status and laboratory results from the RCT. We evaluated circumcised and uncircumcised men's sexual behavior using an 18-item risk propensity score and acquisition of incident infections of gonorrhea, chlamydia, and trichomoniasis. Of 1780 eligible RCT participants, 1319 enrolled (response rate = 74%). At the baseline RCT visit, men who enrolled in the sub-study reported the same sexual behaviors as men who did not. We found a significant reduction in sexual risk behavior among both circumcised and uncircumcised men from baseline to 6 (p<0.01) and 12 (p = 0.05) months post-enrollment. Longitudinal analyses indicated no statistically significant differences between sexual risk propensity scores or in incident infections of gonorrhea, chlamydia, and trichomoniasis between circumcised and uncircumcised men. These results are based on the most comprehensive analysis of risk compensation yet done.In the context of a RCT, circumcision did not result in increased HIV risk behavior. Continued monitoring and evaluation of risk compensation associated with circumcision is needed as evidence supporting its' efficacy is disseminated and MC is widely promoted for HIV prevention

Effects of Genital Ulcer Disease and Herpes Simplex Virus Type 2 on the Efficacy of Male Circumcision for HIV Prevention: Analyses from the Rakai Trials

Ron Gray and colleagues analyze data from two circumcision trials in Uganda to assess how HSV-2 status and genital ulcer disease affect the procedure's ability to reduce HIV infection

HIV-1 Efficient Entry in Inner Foreskin Is Mediated by Elevated CCL5/RANTES that Recruits T Cells and Fuels Conjugate Formation with Langerhans Cells

Male circumcision reduces acquisition of HIV-1 by 60%. Hence, the foreskin is an HIV-1 entry portal during sexual transmission. We recently reported that efficient HIV-1 transmission occurs following 1 h of polarized exposure of the inner, but not outer, foreskin to HIV-1-infected cells, but not to cell-free virus. At this early time point, Langerhans cells (LCs) and T-cells within the inner foreskin epidermis are the first cells targeted by the virus. To gain in-depth insight into the molecular mechanisms governing inner foreskin HIV-1 entry, foreskin explants were inoculated with HIV-1-infeceted cells for 4 h. The chemokine/cytokine milieu secreted by the foreskin tissue, and resulting modifications in density and spatial distribution of T-cells and LCs, were then investigated. Our studies show that in the inner foreskin, inoculation with HIV-1-infected cells induces increased CCL5/RANTES (1.63-fold) and decreased CCL20/MIP-3-alpha (0.62-fold) secretion. Elevated CCL5/RANTES mediates recruitment of T-cells from the dermis into the epidermis, which is blocked by a neutralizing CCL5/RANTES Ab. In parallel, HIV-1-infected cells mediate a bi-phasic modification in the spatial distribution of epidermal LCs: attraction to the apical surface at 1 h, followed by migration back towards the basement membrane later on at 4 h, in correlation with reduced CCL20/MIP-3-alpha at this time point. T-cell recruitment fuels the continuous formation of LC-T-cell conjugates, permitting the transfer of HIV-1 captured by LCs. Together, these results reveal that HIV-1 induces a dynamic process of immune cells relocation in the inner foreskin that is associated with specific chemokines secretion, which favors efficient HIV-1 entry at this site

Setting the stage: host invasion by HIV.

For more than two decades, HIV has infected millions of people worldwide each year through mucosal transmission. Our knowledge of how HIV secures a foothold at both the molecular and cellular levels has been expanded by recent investigations that have applied new technologies and used improved techniques to isolate ex vivo human tissue and generate in vitro cellular models, as well as more relevant in vivo animal challenge systems. Here, we review the current concepts of the immediate events that follow viral exposure at genital mucosal sites where most documented transmissions occur. Furthermore, we discuss the gaps in our knowledge that are relevant to future studies, which will shape strategies for effective HIV prevention

Short-chain fatty acids increase expression and secretion of stromal cell-derived factor-1 in mouse and human pre-adipocytes

Objective: Stromal cell-derived factor-1 (SDF-1) is expressed in pre-adipocytes but its role is unknown. We investigated butyrate (a histone deacetylase inhibitor - HDACi) and other short-chain fatty acids (SCFA) in the regulation of SDF-1. We further investigated whether effects of SCFA were signalled through G protein-coupled receptors FFA2 and FFA3. Design and Results: SDF-1 mRNA expression and protein secretion were studied in 3T3-L1 cells and human pre-adipocytes. SDF-1 was abundant, with mRNA and protein levels increased by butyrate. This was replicated with acetate and propionate, but not with trichostatin or valproate. Trichostatin inhibited SDF-1 secretion. Pertussis toxin blocked stimulation by butyrate. The order of potency of SCFA in stimulating SDF-1 (C3 &gt; C4 &gt; C2) is consistent with action through FFA3. Silencing the FFA3 gene abolished butyrate-stimulated SDF-1 expression and secretion. FFA3 was expressed in both pre-adipocytes and adipocytes, while FFA2 was expressed in adipocytes only. SDF-1 expression was low in murine macrophage J774.2 cells, while the SDF-1 receptor CXCR4 was absent from 3T3-L1 cells but abundant in J774.2 macrophages. In human pre-adipocytes, FFA3 was also expressed and SCFA increased SDF-1 secretion. Conclusions: SDF-1 and CXCR4 may mediate the interaction between adipose stromal cells and macrophages. Effects of SCFA are mediated through FFA3, but not histone deacetylase inhibition