Medroxyprogesterone Acetate Regulates HIV-1 Uptake and Transcytosis but Not Replication in Primary Genital Epithelial Cells, Resulting in Enhanced T-Cell Infection

Abstract

Although clinical and experimental evidence indicates that female sex hormones and hormonal contraceptives regulate susceptibility to human immunodeficiency virus type 1 (HIV-1) infection, the underlying mechanism remains unknown. Genital epithelial cells (GECs) are the first cells to encounter HIV during sexual transmission and their interaction with HIV may determine the outcome of exposure. This is the first report that HIV uptake by GECs increased significantly in the presence of the hormonal contraceptive medroxyprogesterone acetate (MPA) and progesterone and that uptake occurred primarily via endocytosis. No productive infection was detected, but endocytosed virus was released into apical and basolateral compartments. Significantly higher viral transcytosis was observed in the presence of MPA. In GEC and T-cell cocultures, maximum viral replication in T cells was observed in the presence of MPA, which also broadly upregulated chemokine production by GECs. These results suggest that MPA may play a significant role in regulating susceptibility to HIV.

Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections

“…Previously, several studies had indicated that P 4 or its synthetic form increased HIV-1 susceptibility or risk of infection (Asin et al 2008, Ramjee & Wand 2012, Ferreira et al 2014) in a macaque model using subcutaneous implants of P 4 which increased vaginal SIV transmission several fold (Marx et al 1996). Similar to these earlier studies, we also observed that treatment with steroid hormones increased HIV-1 viral load levels in culture supernatants.…”

Is a lower-dose, subcutaneous contraceptive injectable containing depot medroxyprogesterone acetate likely to impact women's risk of HIV?

“…For example, in mice MPA at 4–7 nM decreases genital tract barrier function with an increased susceptibility to HSV-2 viral infection [59]. E x vivo data are broadly consistent with results from animal studies; MPA appears to increase HIV-1 proliferation in human immune cells at about 0.1 nM [72], dampen the function of immune cells at 0.3 nM [73], increase transcytosis of HIV-1 across the FGT epithelial cells at 1 nM [74], and decrease expression of select immunomodulators by FGT epithelial cells at 1–20 nM [74, 75]. The relative roles of the GR and PR in these mechanisms is not established, although MPA has been shown in vitro to regulate expression of immunomodulators and the function of immune cells via the GR [54, 75–79].…”

HIV internalization into oral and genital epithelial cells by endocytosis and macropinocytosis leads to viral sequestration in the vesicles

“…Cells were also treated with amiloride, which inhibits macropinocytosis (Ivanov, 2008a; Saeed et al, 2010). These drugs are widely used for blocking endocytosis and macropinocytosis by many viruses, including HIV (Carter et al, 2011, 2009; Daecke et al, 2005; Dorosko and Connor, 2010; Ferreira et al, 2015; Grigorov et al, 2006; Kinlock et al, 2014; Liu et al, 2002; Mikulak et al, 2009; Miyauchi et al, 2009; Platt et al, 2014; Sloan et al, 2013). After 1 h of treatment, dual-tropic HIV-1 SF33 internalization was examined from the apical (AP) surface of epithelium by p24 ELISA.…”

“…HIV-1 has been detected in the endosomes, MVB, and vacuoles of epithelial cells (Daecke et al, 2005; Dorosko and Connor, 2010; Ferreira et al, 2015; Grigorov et al, 2006; Kinlock et al, 2014; Mikulak et al, 2009; Orenstein, 2007; Tugizov et al, 2011; Yasen et al, 2017). However, critical extra- and intraepithelial molecules regulating vesicular trafficking of virions are still poorly investigated.…”

“…To quantify the integrated viral DNA, we used real-time qPCR as described by Suzuki et al (Ferreira et al, 2015). The first PCR product was subsequently diluted fourfold and subjected to qPCR using the HIV-1 R/U5 region.…”