Does HIV Exploit the Inflammatory Milieu of the Male Genital Tract for Successful Infection?

Abstract

In many parts of the World, medical male circumcision (MMC) is used as standard prevention of care against HIV infection. This is based on seminal reports made over 10 years ago that removal of the foreskin provides up to 60% protection against HIV infection in males and seems currently the best antiretroviral-free prevention strategy yet against the global epidemic. We explore the potential mechanisms by which MMC protects against HIV-1 acquisition and that one of the oldest, albeit re-invented, rituals of removing a foreskin underscores the exploitative nature of HIV on the anatomy and tissue of the uncircumcised penis. Furthermore, foreskin removal also reveals how males acquire HIV, and in reality, the underlying mechanisms of MMC are not known. We argue that the normal sequelae of inflammation in the male genital tract (MGT) for protection from sexually transmitted infections (STI)-induced pathology represents a perfect immune and microbial ecosystem for HIV acquisition. The accumulation of HIV-1 target cells in foreskin tissue and within the urethra in response to STIs, both during and after resolution of infection, suggests that acquisition of HIV-1, through sexual contact, makes use of the natural immune milieu of the MGT. Understanding immunity in the MGT, the movement of HIV-1 target cells to the urethra and foreskin tissue upon encounter with microbial signals would provide more insight into viral acquisition and lay the foundation for further prevention strategies in males that would be critical to curb the epidemic in all sexual partners at risk of infection. The global female-centric focus of HIV-1 transmission and acquisition research has tended to leave gaps in our knowledge of what determines HIV-1 acquisition in men and such understanding would provide a more balanced and complete view of viral acquisition.

Keywords: HIV-1; acquisition; exploitation; inflammation; medical male circumcision; risk factors; sexually transmitted infections.

Figure 1

Factors affecting HIV infection of the male genital tract. (A) The foreskin consists of a double layer of stratified epithelium that covers the glans/corona and meatus of a flaccid penis. (B) Circumcision results in the removal of the majority of the foreskin epithelium leaving a “dry” keratinized surface that is assumed to be resistant to HIV infection. Non-STI genital microbial populations have been shown to modulate genital inflammation through the antigen recognition, which may result in migration or activation of HIV target cells into the foreskin. Circumcision results in a removal of the moist sub-preputial space and decrease in anaerobic bacterial species, which are likely pro-inflammatory. (C) The foreskin is a stratified epithelium consisting of six epidermal layers namely stratum corneum (SC), stratum granulosum (SG), stratum spinosum (SS), and stratum basale (SB). HIV virions crosses the keratinized (light brown) epithelial border through micro abrasions that occur during sexual intercourse or through the formation of viral synapses between HIV-infected cells and epithelial cells (20). Langerhans’ Cells (LCs) reside within the epidermis where they are the first to encounter the virus (21). Activated LCs migrate into the lower dermal tissues, transferring the virus to resident dermal immune cells such as T cells, macrophages, and epithelial dendritic cells (DCs). Dendritic cells act as professional antigen presenting cells, phagocytosing virions, and migrating to the draining lymph nodes where they present HIV antigens to immature T cells and B cells (22). Intact virus can be trafficked into the lymph nodes by DCs and transferred to CD4⁺ T cells (23) where the virus replicates and is disseminated throughout the body (24). Asymptomatic STIs do not present clinically but inflammation still occurs on a cellular level. The release of pro-inflammatory cytokines by keratinocytes and dermal immune cells in response to an STI would result in recruitment and activation immune cells to the site of infection. This inflammatory environment would result in an accumulation of HIV target cells and therefore increase the efficiency of viral transmission in the case of an HIV infection.