Abstract
To gain insight into female-to-male HIV sexual transmission and how male circumcision protects against this mode of transmission, we visualized HIV-1 interactions with foreskin and penile tissues in ex vivo tissue culture and in vivo rhesus macaque models utilizing epifluorescent microscopy. 12 foreskin and 14 cadaveric penile specimens were cultured with R5-tropic photoactivatable (PA)-GFP HIV-1 for 4 or 24 hours. Tissue cryosections were immunofluorescently imaged for epithelial and immune cell markers. Images were analyzed for total virions, proportion of penetrators, depth of virion penetration, as well as immune cell counts and depths in the tissue. We visualized individual PA virions breaching penile epithelial surfaces in the explant and macaque model. Using kernel density estimated probabilities of localizing a virion or immune cell at certain tissue depths revealed that interactions between virions and cells were more likely to occur in the inner foreskin or glans penis (from local or cadaveric donors, respectively). Using statistical models to account for repeated measures and zero-inflated datasets, we found no difference in total virions visualized at 4 hours between inner and outer foreskins from local donors. At 24 hours, there were more virions in inner as compared to outer foreskin (0.0495 +/− 0.0154 and 0.0171 +/− 0.0038 virions/image, p = 0.001). In the cadaveric specimens, we observed more virions in inner foreskin (0.0507 +/− 0.0079 virions/image) than glans tissue (0.0167 +/− 0.0033 virions/image, p<0.001), but a greater proportion was seen penetrating uncircumcised glans tissue (0.0458 +/− 0.0188 vs. 0.0151 +/− 0.0100 virions/image, p = 0.099) and to significantly greater mean depths (29.162 +/− 3.908 vs. 12.466 +/− 2.985 μm). Our in vivo macaque model confirmed that virions can breach penile squamous epithelia in a living model. In summary, these results suggest that the inner foreskin and glans epithelia may be important sites for HIV transmission in uncircumcised men.
Highlights
The World Health Organization estimates that over 35 million people world-wide are currently infected with the human immunodeficiency virus (HIV)[1]
Several clinical trials have demonstrated that male circumcision can protect men from becoming infected with HIV, we know very little about how men get infected through sex and how circumcision changes this
We explored possible sites of virus transmission across the penis by looking at how HIV interacts with adult male foreskins, penile tissues from circumcised and uncircumcised cadavers, and male rhesus macaques
Summary
The World Health Organization estimates that over 35 million people world-wide are currently infected with the human immunodeficiency virus (HIV)[1]. Male circumcision has been shown to effectively reduce the risk of HIV acquisition in men by 50–60% in three large African cohorts[3,4,5]. This protective effect appears to be long-lasting and extends to other sexually transmitted infections (STIs) such as human papillomavirus and herpes simplex virus-2[6]. We sought to explore potential sites of HIV transmission through the penis using tissue explants from adult donors and a living rhesus macaque model
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