CHAPTER 5: In vivo and in vitro effects of injectable hormonal contraceptives on
6.2 Introduction
The mucosal epithelium of the lower female reproductive tract provide the first line of defence against pathogen entry and mediate the initial host immune response against STIs, including HIV-1 (Kaushic, 2011; Wira et al., 2005a; Wira et al., 2005b). This is also the surface through which HIV-1 is transmitted from an HIV-1 infected women to her sexual partner (Yi et al., 2013). The genital mucosa is also thought to serve as a discrete site for HIV-1 infection, replication and pathogenesis by providing the virus with a steady supply of susceptible target cells (Zhang et al., 1999).
The epithelial barrier of the genital mucosa is also thought to be influenced by hormones, inflammation and infection (Murphy et al., 2014). Studies in naturally cycling non-human primates have demonstrated the effect of hormones on the vaginal epithelium during the menstrual cycle, reporting a thicker epithelial barrier during the estrogen-dominant follicular phase and thinner epithelia during the progesterone-dominant luteal phase (Poonia et al., 2006; Veazey et al., 2012). Non-human primate studies have also suggested dramatic atrophy of the vaginal epithelium following administration of DMPA, although the amounts of DMPA used in these models is generally much higher than typically used in humans per kilogram body weight (Smith et al., 2000; Smith et al., 2004; Trunova et al., 2006). A similar but less pronounced hormonal effect on vaginal epithelial thickness is seen in humans, with decreased number of epithelial layers or reduced barrier thickness being reported during the luteal than follicular phase in naturally cycling women (Mauck et al., 1999; Patton et al., 2000) and in women using DMPA (Mauck et al., 1999). In both humans and non-human primate studies, thinning of the genital tract epithelium during either the luteal phase of the menstrual cycle or in those treated with DMPA, has been associated with increased
susceptibility to certain STIs, including HIV-1, HPV and C. trachomatis (Baeten et al., 2005;
Marx et al., 1996).
DMPA may alternatively contribute to HIV-1 pathogenesis by facilitating closer contact between target cells in the mucosa and HIV-1 particles because of thinner epithelium (Chandra et al., 2013; Ildgruben et al., 2003; Miller et al., 2000; Wieser et al., 2001; Wira et al., 2011b). DMPA may influence the density of intracellular junction proteins between epithelial cells, potentially allowing better penetration of HIV-1 and facilitating better contact with mucosal target cells (Chandra et al., 2013). Chandra et al. (2013) showed that vaginal biopsies from HIV-1 uninfected women treated with DMPA had higher numbers of CD4+ T cells and macrophages expressing HLA-DR and CCR5 than non-HC counterparts. However, earlier studies reported no link between recruitment or activation of HIV-1 susceptible target cells and injectable HC use, despite resulting in decreased epithelial thickness (Bahamondes et al., 2000; Bahamondes et al., 2014; Kiddugavu et al., 2003; Mauck et al., 1999; Myer et al., 2007).
Acute HIV-1 infection has been associated with increased genital tract inflammatory cytokine responses in women (Roberts et al., 2012), that may result in increased permeability of the mucosal epithelial barrier, allowing HIV-1 easier passage across the mucosal epithelium (Nazli et al., 2010). Inflammatory responses at the genital mucosa have also been shown to enhance HIV-1 pathogenesis, by recruiting highly-activated HIV-1 target cells to the site of initial viral infection and replication (Abel et al., 2005; Li et al., 2009; Meier et al., 2007). In DMPA-treated macaques infected with SIV, cervicovaginal concentrations of MIP-1α, MIP- 1β and MIP-3α resulted in recruitment of CCR5+ and CD4+ T cells in the endocervical
epithelium (Li et al., 2009). Furthermore, spread of SIV-infected cells from the genital mucosa to ensure a productive systemic infection, correlated with this pro-inflammatory cytokine gradient (Li et al., 2009). In humans, concentrations of IL-1β, IL-6, and IL-8 in CVLs from HIV-1 acutely infected women correlated inversely with CD4+ T cell counts in blood, suggesting the level of genital inflammation present during acute infection predicted adverse CD4 decline during acute infection (Bebell et al., 2008). Increased recruitment of activated HIV-1 target cells to the genital epithelium was shown to facilitate local HIV-1 replication and result in increased local genital HIV-1 shedding from HIV-1 infected women, potentially placing their male partners at higher risk of HIV-1 infection (Gordon et al., 1999;
Rottman et al., 1997). In both humans and non-human primates studies, higher levels of T cell activation in blood and plasma viral loads during acute infection predicted faster rates of mucosal and systemic CD4 cell decline and more accelerated disease progression (Brenchley et al., 2004; Douek et al., 2009; Hazenberg et al., 2003; Silvestri et al., 2003).
The aim of this Chapter was to investigate the effect of injectable HC use on vaginal epithelial thickness, availability or depth of HIV-1 targets cells at the genital mucosa and the rate of HIV-1 disease progression (higher viral loads at set-point and CD4 decline to 12 months post-infection) during acute HIV-1 infection. A better understanding of the impact of injectable HC use on density and depth of activated HIV-1 target cells at the mucosa in the presence of genital inflammation during acute infection could lead to better interventions aimed at blocking HIV-1 transmission from an infected women to her partner. In addition, it would also identify therapeutic targets to block male-to-female transmission.