HIV‐1 Transmission in the Male Genital Tract

Abstract

HIV-1 is mainly a sexually transmitted infection, and epithelial surfaces covering genital mucosa are the primary site of HIV-1 transmission. Although male circumcision was reported to reduce male acquisition of HIV-1 by 60%, the initial mechanisms of HIV-1 transmission in the male genitals remain elusive. We established two novel models of the adult human foreskin epithelium that allowed for polarized infection via the mucosal pole with either HIV-1-infected cells that are present in all secretions vectorizing HIV-1 or cell-free HIV-1. Efficient HIV-1 transmission occurs following 1 hr of polarized exposure of the inner, but not outer, foreskin to mononuclear cells highly infected with HIV-1, but not to cell-free virus. HIV-1-infected cells form viral synapses with apical foreskin keratinocytes, leading to polarized budding of HIV-1, which is rapidly internalized by Langerhans cells (LCs) in the inner foreskin. In turn, LCs form conjugates with T-cells, thereby transferring HIV-1. Seminal plasma from HIV-negative men mixed with cervico-vaginal secretions from HIV-positive women, which mimics the in-vivo mixture of these genital fluids during woman-to-man HIV-1 sexual transmission, decreases HIV-1 infection at the foreskin. Our results rationalize at the cellular level the apparent protective outcome of circumcision against HIV-1 acquisition by men.

Human/Simian Immunodeficiency Virus Transmission and Infection at Mucosal Sites

“…Also, in foreskin explants, epidermal Langerhans cells have been found to play a key role in transmission (Ganor et al, 2010;Ganor and Bomsel, 2011;Zhou et al, 2011), whereas they seem less critical in vaginal transmission in studies using reconstructed human vaginal mucosa in vitro (Bouschbacher et al, 2008).…”

Human Male Genital Tract Immunity

“…Furthermore, since the entire tip of the penis, including the urethral opening, is protected by the foreskin and is influenced by the subpreputial microenvironment, sites other than the inner foreskin (for example, the meatus and penile urethra) may also be more susceptible to HIV infection in noncircumcised men. These sites are also probable sites of HIV infection in circumcised men (Anderson et al, 2011;Ganor and Bomsel, 2011).…”

A Perspective on Progress and Gaps in HIV Prevention Science

“…The mechanism and extent to which virus directly crosses the epithelium or is captured by immune cells remain controversial and likely vary at different anatomic sites. [30][31][32][33][34][35] The small infected founder population, which in macaque models is composed mainly of resting CD4 T cells, 36,37 expands locally, resulting in dissemination of virus to draining lymph nodes and subsequently through the bloodstream to establish infection in secondary lymphoid organs. Precisely how virus (cell-free or cell-associated) reaches submucosal immune target cells and the inoculum required are all areas of intense investigation.…”