The Structure and the Role of Mucosal Epithelia in the Initial Steps of HIV-1 Infection
HIV-1 is a viral menace that gains access into the body mainly during sexual intercourse, by crossing epithelial barriers that cover the mucosal surfaces of the gastrointestinal, female, and male genital tracts. These mucosal epithelia have evolved to provide different levels of protection from incoming foreign molecules and pathogens. Stratified epithelia that underlay areas of opening and contact with the external environment are made of multiple layers of epithelial cells,1 providing a high degree of mechanical barrier and defense against bacterial and viral insults originating from the external environment. Moreover, various immune cells, such as Langerhans cells (LCs), T-cells, dendritic cells (DCs), and macrophages (which are either inserted between the epithelial cells or reside within the lamina propria), further enable the specific recognition of pathogens and the subsequent engagement of the immune system to eliminate rapidly and efficiently these invading threats. In contrast, simple epithelia covering mucosal surfaces within the body consist of monolayers of polarized epithelial cells connected by tight junctions,1 as well as various immune cells residing below the epithelial barrier. These simple mono-layered epithelia provide a lower degree of protection.
How does HIV-1 cross epithelial barriers and gain access into the body? Many studies addressing this question have clearly demonstrated that HIV-1 utilizes different mechanisms to enter the body via the mucosa, depending on the type of epithelial barrier it encounters. Thus, it seems that HIV-1 has evolved to ‘highjack’ existing physiological processes in mucosal epithelia to invade the body: pathogen recognition by LCs in stratified epithelia and transcytosis in simple epithelia.
Hence, in the vagina and exocervix stratified epithelia, early HIV-1 transmission involves capture of HIV-1 by epidermal LCs. These professional antigen-presenting cells, integrated within these epithelia, normally sample the mucosal surface for incoming foreign pathogens and then migrate to secondary lymphoid organs to present processed antigens to T-cells.2 LCs are among the first cells to capture HIV-1, because of their close proximity to the mucosal surface and their ability to bind the HIV-1 envelope glycoprotein subunit gp120 via their unique C-type lectin langerin.3–5 At low viral concentrations, this process leads to HIV-1 degradation by LCs.5 However, at higher concentrations of the virus, the protective effect of langerin is inhibited,5 leading to the subsequent transfer of the internalized virus to T-cells and the productive infection of T-cells,6,7 either locally within the epithelium or in the draining lymph nodes following LCs migration.
In contrast, in the rectum, intestine, and endocervix simple epithelia, we and others have shown that HIV-1 crosses in-vitro the epithelial barrier by the transcellular pathway of transcytosis.8–12 This process involves the formation of an apical transient contact, the ‘viral synapse’, between HIV-1-infected cells and epithelial cells, which induces polarized virus budding at the contact area between the two cell types.8,11,13,14 The newly budded virus is then rapidly internalized by the epithelial cells (without productively infecting them, as is the case in-vivo), transcytosed towards the basal pole, and released still infectious to the basal environment.8
Transmission of Cell-associated versus Cell-free HIV-1
Early studies including our own have shown that HIV-1 transcytosis across simple epithelia is much more efficient, when HIV-1 particles bud locally at viral synapses compared to cell-free HIV-1.8,11,13–16 Notably, all genital fluids that transmit HIV-1, such as seminal plasma (SP) and cervicovaginal secretions (CVS), contain HIV-1-infected cells. For example, SP contains on the order of 105 white blood cells/mL with substantial numbers of macrophages and CD4+ T-cells.17 In HIV-1-infected men, the infection rate of this seminal HIV-1-susceptible cell population was estimated at 0.2%.17 Similarly, several studies documented HIV-1-susceptible host cells in CVS and demonstrated the presence of HIV-1 DNA or RNA and the ability to culture the virus from the cell-associated fractions.17 A recent study showed that systemic and persistent infection could be achieved in female macaques following vaginal exposure to SIV-infected cells.18 These observations clearly emphasize the importance of cell-associated HIV-1 as a major and efficient transmission vector. Yet, most research on mucosal HIV-1 transmission has focused on cell-free HIV-1, probably because of the ease in preparing and manipulating cell-free HIV-1 compared to cell-associated HIV-1. Therefore, further studies are still urgently needed to better characterize the cellular and molecular events underlying cell-associated HIV-1 transmission.
The Biology of Sexual Intercourses and its Relevance to HIV-1 Transmission
As mentioned earlier, sexual transmission of HIV-1 is mediated in-vivo by genital fluids (e.g. SP and CVS). Previous studies have shown that SP induces secretion of chemokines by epithelial cells of the female genital mucosa, leading to subsequent transient attraction of mononucleated cells,19 which may in turn increase the susceptibility to HIV-1 infection. However, recent in-vitro studies investigating the effect of SP on HIV-1 transmission have reached contradictory conclusions, demonstrating that endogenous factors in SP may either enhance20 or inhibit21 HIV-1 infection and transfer to T-cells. Other studies have shown that CVS contain a plethora of protective innate factors against HIV-1.22–30 Although these studies clearly suggest that genital fluids may directly affect HIV-1 transmission, their role in mucosal HIV-1 infection models is rarely evaluated.
Importantly, the sexual transmission of HIV-1 is also facilitated by several sexually transmitted diseases (STDs). Longitudinal epidemiological studies have provided direct evidence that STDs in HIV-1-uninfected individuals increase their risk of acquiring HIV-1.31,32 However, it has been difficult to determine which STD has the greatest effect on HIV-1 transmission. For instance, Chlamydia trachomatis and Neisseria gonorrhoeae are common exclusive human STD pathogens, which primarily infect the urogenital epithelia, i.e. the urethra in men and the cervix in women, and cause mucosal inflammation.33–36 Both pathogens can invade their target epithelial cells, resulting in production of proinflammatory cytokines by the infected cells and subsequent influx of various immune cells to the infection site.35,37,38 While this process may further increase the amount of potential HIV-1 target cells, the exact details of the interplay between various STD pathogens and HIV-1 in mucosal epithelia are to a large extent unknown.