HIV entry into cells: The role of male circumcision

T helper cells act as the ‘loud-speakers’ of the immune system, activating cytotoxic T cells that destroy virus-infected cells, and B cells that produce antibodies. HIV destroys Helper T cells, causing immune system suppression. The virus fuses with cell surface molecules before it enters the cell. HIV is much more stable within cells than in the blood. Outside of cells it is also very sensitive to environmental damage. Transfer of cells is more effective in transmitting the virus. Baeten and co-workers (2) in 2005 showed that the overall female-to-male probability of HIV-1 acquisition per sex act was 0.0063 (95% confidence interval, 0.0035-0.0091). After binding to the CD4 molecule, HIV binds another cell surface molecule, a chemokine receptor known as CCR5. CCR5 is the ‘door-knob’ that allows efficient entry of HIV into target cells. But some individuals have defective CCR5 genes making them genetically resistant to HIV infection, regardless of exposure. CCR5 mutations provide a molecular explanation of the so-called discordant couples, where one partner is HIV-positive while the other is completely negative despite having unprotected sex. The question whether male circumcision can prevent HIV was first sparked by Fink in 1986 who claimed that hardening (keratinization) of the circumcised male genitals reduced the chance of HIV penetration (6). Epidemiological data have suggested that male circumcision is a major protective factor against male heterosexual HIV transmission and may explain the significant geographic differences in the prevalence of HIV observed within sub-Saharan Africa (8). As early as 1994, there were over 30 epidemiological studies on HIV transmission and circumcision (12). Eighteen cross-sectional studies from the Cote d’Ivoire, Kenya, Rwanda, Uganda, US, and Zambia reported a significant association between the presence of the foreskin and risk for HIV infection (odds ratio = 2.4; p =0.05 among male sexually transmitted disease patients in Zambia). The foreskin increases biological susceptibility to HIV infection through a number of mechanisms: increased presence of inflammatory conditions, with resultant mucosal discontinuity and/or increased local lymphocyte recruitment; increased occurrence of scratches, tears and abrasions during sexual intercourse; providing portals of entry for the virus; the presence of a warm, moist environment under the foreskin which is conducive to viral survival; and keratinisation of the exposed glans of the circumcised versus the uncircumcised male organs (13). However, studies are just beginning to focus on the biological mechanisms by which the foreskin may increase HIV susceptibility. A study of thirteen cadavers in Australia found there were no differences in the keratin layer covering the glans of the circumcised versus the uncircumcised male organs (13). The mechanism by which HIV enters a host through mucosa has been most extensively studied in the female genital tract, in both animal models and humans (10, 14, 9). Much less is known about simian immunodeficiency virus or HIV transmission in the male genital tract. In animal models, inoculation of SIV on the mucosa of the penis in macaques resulted in infection of Langerhans cells, primary target cells for HIV (14). Langerhans cells have been found at high densities in the inner but not outer mucosal surface of the human foreskin (10, 5). The density of Langerhans cells in the epithelium of the circumcised penile shaft is unknown. Recently, the outer surface of foreskin tissues taken from US infants and adults in Chicago was shown to be highly keratinised whereas on the inner surface there was no or little keratinisation (5). HIV target cells (CD4 T cells, Langerhans cells, and macrophages) were identified on the inner, mucosal surface of foreskin tissue at densities six times higher than in cervical tissue and these cells were demonstrated to express CCR5. The inner surface of the foreskin is highly susceptible to HIV infection compared with the outer keratinised surface, which is likely to be similar to the epithelium of the circumcised male genitals (5). In 2005, a review of the medical literature supporting mass circumcision for the prevention of HIV infection found the literature to be inconsistent and based on observational studies, not randomised controlled trials (16). A study by Auvert and others (1) in 2001 found that in Ndola, Zambia, the prevalence of HIV infection was not significantly different between circumcised (25%) and uncircumcised men (26.0%). These results were probably misleading because the frequency of circumcised men in Ndola was very low (9%). However, in Kisumu, Kenya, the prevalence of HIV infection was 9.9% among circumcised men and 26.6% among uncircumcised men (1). According to Buve (4), the differences in HIV prevalence in African cities cannot be explained by differences in sexual behaviour. Differences in sexual behaviour were outweighed by differences in factors that influence HIV transmission especially male circumcision; thus circumcision is an important intervention for HIV/AIDS. Inungu and others (11) have also criticised African studies linking male circumcision to HIV protection. They argued that these studies’ systematic lack of control of important confounding factors make the assessment of the association between male circumcision and HIV transmission very difficult and raises doubt about the validity of the findings. They emphasised that randomized controlled trials were needed to determine the true strength of the association, and until then, a decision to recommend mass male circumcision to prevent HIV transmission in sub-Saharan Africa was premature and risky (11). In Kenya, uncircumcised men were at a more than 2-fold increased risk of acquiring HIV-1 per sex act compared with circumcised men (2). Female-to-male infectivity was significantly higher for uncircumcised men than for circumcised men (0.0128 vs. 0.0051; P=0.04). The effect of circumcision was robust in subgroup analyses and across a wide range of HIV-1 prevalence estimates for sex partners. Donoval and co-workers (5) examined biological mechanisms that increase susceptibility of uncircumcised African men to HIV-1. They reported that the densities and positions of HIV-1 target cells (Langerhans, CD4 cells) in the foreskin tissue of Kenyan men indicate that the inner mucosal surface of the human foreskin contains cells that make it highly susceptible to HIV infection. There is considerable interest in the potential link between male circumcision and a lower risk of HIV acquisition. In 2005, a trial in Gauteng province in South Africa among men aged 18-24 years showed promising protective effects of adult male circumcision in reducing HIV acquisition (15). But more research is needed to confirm the reproducibility of the findings of this trial and whether or not the results have more general application (15). As a result of increased desire for male circumcision in a bid to prevent HIV infection, UNAIDS recommended that governments should take steps to ensure that male circumcision is conducted by trained practitioners in safe and equipped settings in order to reduce the rate of post-operative complications (15). l Chinsembu is a lecturer in the Department of Biology, University of Namibia, Windhoek. Email: kchinsembu@unam.na l To be continued next week

May 2006
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