Channels • 2022 • Volume 6 • Number 2 Page 3 HIV-1 strains, HIV-1 is categorized into groups M, N, O, and P (though only group M is of major concern due to it being responsible for the worldwide pandemic). There are also several subtypes (“clades”) of HIV-1 including, most-notably, Clade C - which is responsible for over half of all HIV-1 infections world-wide and is especially concentrated in sub- Saharan Africa (Shaw & Hunter, 2012). Now that the virus is capable of pathogenicity in humans, it is transmitted between humans via a multitude of ways - namely, through infectious bodily fluids. Examples of these fluids include blood, semen, rectal fluids, vaginal fluids, and breast milk (Centers for Disease Control and Prevention). Transmission of HIV, however, is not a unilateral process - not only must an uninfected individual encounter infectious fluid, but those infectious fluids must be able to cross mechanical barriers of a new host’s immune system. The most commonly breached mechanical barriers are mucous membranes in various regions of the body. Specifically, one of the most vulnerable mucosal membranes to HIV-1 infection is the anal/rectal mucosa - though vaginal epithelium, urethral epithelium, and the penile cutaneous membrane are also vulnerable to HIV-1 but to a lesser degree. Anal/rectal mucosa is particularly susceptible, because the epithelial layer within this mucosa is composed of only a single layer of simple columnar epithelium (as opposed to the stratified squamous epithelium of the vaginal mucosa and the keratinized stratified squamous epithelium of the penile skin.) This means that micro lacerations, which expose underlying, vulnerable MALT (mucosa-associated lymphoid tissues) underneath the mucosal layers, have a greater propensity to form within the thin anal/rectal mucosa’s epithelium as opposed to other, thicker mucosa’s epithelial layers (Fox & Fiddler, 2010; Gonzalez et al., 2019). Since the anal/rectal mucosa is so susceptible, it serves as a good example for the first mechanistic phases of HIV-1 pathogenesis. As mentioned previously, one way in which HIV- 1 can cross the anal/rectal mucosa is via micro lacerations (physical tears) in the mucosa itself, allowing HIV-1 viral particles to gain access to the rectal MALT, subsequently leading to the beginning of Acute Infection in resting memory CD4+ T-cells (bystander Helper T- cells) within the MALT. There are, however, alternative means by which HIV-1 viral particles can gain access to the underlying MALT. First, viral particles can simply be transported across the simple columnar epithelium via transcytosis, subsequently coming out of the basal aspect of the epithelium and into the vulnerable MALT. Alternatively, intraepithelial lymphocytes (specifically CD4+ T-cell subtypes) can be directly infected by viral particles approaching the epithelium from the rectal lumen. Furthermore, viral particles can take advantage of microfold cells (Mcells), which normally transcytosis potential antigens to the underlying MALT, via the M-cells’ tendency to simply transcytosis the viral particles through the epithelium and into the MALT. Finally, and most interestingly, HIV-1 can utilize the normal immunological function of local, mucosaresident Dendritic Cells (DCs) in order to pass through the epithelium to gain access to local MALT, as well achieving longer-distance dissemination within the body (Fox & Fiddler, 2010). HIV-1 is capable of binding to a specific Type II Fc R (Fc-receptor) on DCs called
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