Abstract
We compared outer and inner foreskin tissue from adolescent males undergoing medical male circumcision to better understand signals that increase HIV target cell availability in the foreskin. We measured chemokine gene expression and the impact of sexually transmitted infections (STIs) on the density and location of T and Langerhans cells. Chemokine C–C ligand 27 (CCL27) was expressed 6.94-fold higher in the inner foreskin when compared with the outer foreskin. We show that the density of CD4+CCR5+ cells/mm2 was higher in the epithelium of the inner foreskin, regardless of STI status, in parallel with higher CCL27 gene expression. In the presence of STIs, there were higher numbers of CD4+CCR5+ cells/mm2 cells in the sub-stratum of the outer and inner foreskin with concurrently higher number of CD207+ Langerhans cells (LC) in both tissues, with the latter cells being closer to the keratin surface of the outer FS in the presence of an STI. When we tested the ability of exogenous CCL27 to induce T-cell migration in foreskin tissue, CD4 + T cells were able to relocate to the inner foreskin epithelium in response. We provide novel insight into the impact CCL27 and STIs on immune and HIV-1 target cell changes in the foreskin.
Highlights
Three randomised controlled trials (RCTs) in eastern and South Africa demonstrated that Medical Male Circumcision (MMC) provided 52–64% protection from HIV infection[1,2,3] and spurred the roll-out of voluntary MMC as a prevention measure throughout South Africa.[4]
Selection of participants with an asymptomatic sexually transmitted infections (STIs) Up to 42 adolescent males were included in the study, 21 infected with a detectable STI in first pass urine and broken down as follows: Neisseria gonorrheae (NG, n = 1), Chlamydia trachomatis (CT, n = 10) or with CT coinfected with Neisseria gonorrhoeae (NG), MG and MG/NG (n = 4), Trichomonas vaginalis (TV, n = 2), Mycoplasma genitalium (MG, n = 3), HSV-1 and HSV-2 (n = 1)
Chemokine C–C ligand 27 (CCL27) gene expression distinguishes the inner from the outer foreskin We assessed the expression of an array of chemokine genes in the outer and inner foreskin tissue and whether the presence of an STI had an effect on this expression
Summary
Three randomised controlled trials (RCTs) in eastern and South Africa demonstrated that Medical Male Circumcision (MMC) provided 52–64% protection from HIV infection[1,2,3] and spurred the roll-out of voluntary MMC as a prevention measure throughout South Africa.[4]. It is clear that MMC reduces HIV infection in men, the mechanism of circumcision-induced reduction of HIV acquisition is not clear. Understanding mechanisms of MMC-mediated protection against HIV may allow development of alternative options for prevention. Several theories have been posited to explain the protective mechanism of MMC.[5] One is that the inner foreskin is less keratinised than the outer foreskin, having physiological characteristics more similar to mucosal columnar epithelia than the squamous epithelial morphology of the outer foreskin and penile shaft.[6,7] Early qualitative studies seemed to support the hypothesis that the inner foreskin was less keratinised than the outer foreskin,[8,9,10] which may result in easier access to HIV target cells
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